4-Aminopyrimidine-5-carbaldehydes as intermediates in a Friedländer type synthesis of 7-arylpyrido [ 2 , 3-d ] pyrimidines

A study of formylation of 6-aminopyrimidines leads to the conclusion that the formylation at C5 occurs only when there is no contribution of heteroaromaticity in the pyrimidine ring and that the corresponding pyrimidoformamides are formed in heteroaromatic pyrimidines. Once 4aminopyrimidin-4(3H)-one-5-carboxaldehydes were prepared, a series of 7-arylpyrido[2,3d]pyrimidines derivatives were synthesized by a Friedländer type reaction with acetophenones under solvent-free conditions and in the presence of BF3-Et2O. The yields of 7-arylpyrido[2,3d]pyrimidines range from moderate to good and the reaction times were quite short.


Introduction
Nitrogen heterocycles have received a great deal of attention in the literature as a result of their role as pharmacophores of great historical significance.Among these heterocyclic systems, especially those containing pyridine have been the subject of expanding research efforts in heteroaromatic and biological chemistry. 1The pyrido [2,3-d]pyrimidine heterocycles (a.k.a.5deazapteridines), which are those annelated to a pyrimidine ring, are of paramount importance because of their wide range of biological 1a,2 and pharmaceutical applications (i.e., bronchodilators, vasodilators) and their anti-allergic, cardiotonic, antihypertensive, and hepatoprotective activities. 3Some of them have shown properties as antitumour, antibacterial, analgesic or CNS depressants. 4he synthesis of pyrido [2,3-d]pyrimidines has been typically performed by annelation of the pyrimidine ring on the pyridine or vice versa, 5 and these methods include diverse procedures based on the Michael addition-cyclodehydration strategy, 1,5f the three-component one-pot synthesis, 2,6 the route via the aza-Wittig reaction 7 from iodouracils, having a formamidine or acetamidine moiety with various acetylene derivatives. 8Aside from the traditional methodologies, more recent methods include a microwave-assisted one-pot synthesis 3,4c and a procedure that involves ultrasound irradiation without a catalyst. 9Although, the synthesis of this bicyclic system is well documented, most of the synthetic methods rely on cyclocondensation that usually require drastic conditions, long reaction times and complex synthetic pathways.Thus, the search for new, fast routes of synthesis of this kind of molecules remains of considerable importance.
In the course of our synthetic studies of simple nitrogen-containing heterocycles, we have already reported the synthesis of functionalized pyrido [2,3-d]pyrimidines via a selective cyclocondensation reaction between 6-aminopyrimidines and Mannich bases (βdimethylaminopropiophenone hydrochlorides), 3-formylchromone, 2-dimethylaminomethylentetralone hydrochloride, chalcones and methylene-active compounds, 10 and also by using microwaveassisted multicomponent synthesis. 11n the other hand, the Friedländer reaction is a well-known method for the preparation of heteroannulated compounds, 12 and we consider that it is one of the most useful methods for the preparation of pyridopyrimidines and related bicyclic systems.This consists of the reaction between an aromatic or heteroaromatic ortho-amino-carbaldehyde and an aldehyde or ketone bearing an α-methylene moiety.In most cases, this cyclocondensation reaction type was carried out under conventional methods and with longer reaction times.In this way, the possibility of performing reactions under solvent-free conditions is particularly attractive because of its simplicity, lower environmental impact, and minimum reaction time, which can provide a rapid access to large libraries of diverse molecules.
Here we provide a simple and solvent-free method for the preparation of 7-arylpyrido [2,3d]pyrimidines from 6-aminopyrimidines.We have previously prepared the corresponding 6aminopyrimidin-5-carboxaldehydes in order to act as intermediates in a Friedländer reaction type. 13

Results and Discussion
We have tried the preparation of 4-aminopyrimidin-5-carboxaldehydes from 6-aminopyrimidin-4(3H)-ones 2a-d.Two classical formylation reagents, the acetic anhydride/formic acid mixture 14 or the Vilsmeier reagent, 15 have been used (see Scheme 1).The reaction of the 6aminopyrimidines with an acetic anhydride/formic acid mixture led in all cases to the corresponding 6-formamidepyrimidine derivatives 4 in good to excellent yields.
On the other hand, the use of Vilsmeier's reagent rendered different results depending on the starting material, reaction conditions and work-up (Scheme 1).Thus, the formylation at C-5 in the pyrimidine nucleus was effective only when the 3-methyl derivatives 2a,b were used.In the case of the 3H analogues 2c,d, the different attempts of formylation at C5 with Vilsmeier's reagent resulted in all cases in attack at the 6-amino group.Depending on the work-up conditions, one may i) recover the starting material 2c,d, ii) isolate the corresponding amidoderivatives 4c,d or iii) produce the (N,N-dimethyl)amidine derivative 3c (on work-up with ethanol at room temperature for 48 h).
The 1 H NMR spectra of 1, 5a,b and 3g show two broad singlets for the protons of the 4-NH 2 group due to the intramolecular hydrogen bond between the H and the oxygen atom of the 5-CHO group (Experimental and Scheme 1).4-Aminopyrimidine-5-carbaldehydes 1, 5a,b were reacted with acetophenones 7 under different conditions.The use of an equimolar ratio and catalytic amount of BF 3 -Et 2 O (3 drops) through a solvent-free fusion method was appropriate to render the desired 7-arylpyrido [2,3-d]pyrimidines 8 -10 in moderate to good yields within a few seconds.The pyridopyrimidines were filtrated and purified by recrystallization or by column chromatography.
To the best of our knowledge, BF 3 -Et 2 O has been used in the syntheses of several chalcones through a Claisen-Schmidt reaction. 18Here the 7-arylpyrido [2,3-d]pyrimidines were obtained through the initial formation of the corresponding chalcones by an acid-catalyzed Claisen-Schmidt reaction and subsequent intramolecular cyclocondensation between amino and carbonyl groups to give 7-arylpyrido [2,3-d]pyrimidines 8 -10 (Scheme 3).It is important to note that BF 3 -Et 2 O can be used in the presence of ester and amide functional groups.The use of basic catalytic conditions resulted in hydrolysis.On the contrary, the thermal cyclization of compounds 5b occurs through the hydrolysis of the 2-methoxy group to form 10.
Something similar happened in other previous acid reactions in presence of a nucleophile as water formed in the condensation step. 19Compounds 10, which are difficult to produce from the corresponding 6-amino-3-methyluracil, can also be obtained from the 6-amino-3-methyl-2,4dioxo-1,2,3,4-tetrahydro-5-pyrimidinecarbaldehyde 3g.The structures of compounds 8, 9 and 10 were confirmed by spectroscopic analysis.All products show NMR spectra that are in agreement with the proposed structures.The assignment of carbon atoms was based on DEPT-135 measurements along with 2-dimensional HMBC and HSQC ( 1 H-13 C) experiments.All sets of compounds 8 and 9 present similar spectroscopic profiles.For example, in the 1 H NMR spectrum of compound 8a the signals of H-6 and H-5 in the pyridine ring appear at 7.66 and 8.49 ppm respectively as two doublets with J ortho = 8. 03 Hz, and in addition to the heteronuclear correlation observed in the HMBC experiment between signal assigned to C(4) with those to N(3)-CH 3 and H-5.
Regarding compounds 10 the spectroscopic data confirm the hydrolysis of the methoxy group at C(2), the corresponding signal for the H-1 proton of the pyrimidine ring.Finally, the structure of the 7-arylpyrido [2,3-d]pyrimidines was unambiguously confirmed by X-ray diffraction analysis of compounds 8b, 8e, 10c and 10j. 20

Conclusions
We have shown that formylation of 6-aminopyrimidines can occur at the amino group in heteroaromatic pyrimidine systems, and it can occur at C5 if the heteroaromaticity of the pyrimidine ring is low.Using these 5-formylpyrimidine derivatives we have developed a new, rapid and simple methodology for the synthesis of several functionalized pyrido [2,3-d]pyrimidines of potential biological importance in moderate to good yields.This method can be very useful for high-throughput synthesis.A particularly valuable feature of this method consists in the fact that, for the first time, the reaction was catalysed by BF 3 -Et 2 O.The advantages of our method compared to existing methods are short reaction times, solvent-free conditions, low cost and high tolerance of sensitive functional groups such as esters or amides.

Experimental Section
General.Melting points were determined in a Buchi Melting Point Apparatus and are reported uncorrected.The 1 H-and 13 C NMR spectra were measured on Bruker Avance 400 spectrometers operating at 400 and 100 MHz, respectively, and using DMSO-d 6 as solvent and tetramethylsilane as internal standard.The mass-spectra were scanned on a Hewlett Packard HP Engine-5989 spectrometer (equipped with a direct inlet probe) which was operating at 70 eV.High Resolution Mass Spectra (HRMS) were recorded in a Waters Micromass AutoSpec NT spectrometer (STIUJA).The elemental analyses have been obtained using a LECO CHNS-900 and Thermo Finnigan FlashEA1112 CHNS-O (STIUJA) elemental analyzers.
General procedure A for the synthesis of N-pyrimidin-4-yl formamides with acetic anhydride/formic acid mixture 0.5 ml acetic anhydride, 0.15 ml formic acid and 1 mmol of the corresponding 6aminopyrimidine were warmed for the specific time and temperature for each starting aminopyrimidine.The reaction was monitored by TLC (eluent CH 2 Cl 2 -MeOH, 9:1).After reaction of all the aminopyrimidine substrate, the mixture was dried under reduce pressure and the crude product was recrystallized from EtOH.The solid was filtered and washed with cool EtOH.
General procedure B for Vilsmeier formylation of 6-Aminopyrimidines 0.15 ml POCl 3 in 0.5 ml DMF was stirred in an ice bath for 15 minutes.Then, another 1.5 ml DMF and 1 mmol of the corresponding 6-aminopyrimidine were added to the cool solution.The reaction takes place at the corresponding temperature and time for each case.The reaction was monitored by TLC (eluent CH 2 Cl 2 -MeOH, 9:1).After complete comsumption of the aminopyrimidine substrate, the mixture was poured into crushed ice and the solution was allowed to warm to room temperature and then brought to a boil and neutralized with NaOH.The heating continues for an hour and let it cooled to room temperature.The resulting precipitated was filtered, washed with water and recrystallized from EtOH.6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde 1. 0.155 g of 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione reacts according to the general procedure B for 30 minutes at 50 ºC.Yield of 98%, mp 195-198 ºC, bibliographic mp 196-198 ºC. 16