7th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-7), http://www.mdpi.net/ecsoc-7, 1-30 November 2003

[A032]

 

                                                                                          

 

 

The utilization of higher 1,3-cycloalkanediones in the synthesis of 1,4-dihydropyridine ring

 

Marko Milana, Milata Viktorb

 

aZentiva a.s., Nitrianska Street 100, SK-920 27 Hlohovec, Slovak Republic

 

bDepartment of Organic Chemistry, Faculty of Food and Chemical Technology, Slovak Technical University, Radlinského Street 9, SK-812 37 Bratislava, Slovak Republic

 

Keywords: 1,3-diketones;  cyclic diketones;  fused heterocycles preparation;  1,4-dihydropyridines;  Hantzsch pyridine synthesis

 

Abstract: Nonenolizable cyclic diketones such as 1,3-cycloheptanedione and 1,3-cyclooctanedione respectively have been studied in the Hantzsch pyridine synthesis

 

Introduction

 

1,4-Dihydropyridine derivatives I belong to very interesting compounds from the medical point of view. It has been known for a longer time that many of them are calcium chanel modulating agents [1, 2] and therefore valuable drugs for heart disease with useful effects on angina pectoris and hypertension. The most important representatives of this group of drugs are e.g. amlodipine, nifedipine, nimodipine, felodipine and many others.

The most often used approach to 1,4-dihydropyridines is based on the Hantzsch synthesis or on its various modifications, respectively: although there are also known other, less standard methods [3-5]. The original Hantzsch synthesis is the reaction of esters of b-ketoacids with aldehydes and ammonia or a primary amine. On the other hand, esters of b-ketoacid can be replaced by acylacetonitriles, N-substituted acetylacetamides, cyanoacetamide, cyanothioacetamide, 1,3-diketones, their enamines, or appropriatelly combined, for example 1,3-diketones with esters of b-ketoacids. This, in consequence, leads to a very wide scope of the synthesis, leading ultimately to compounds of dihydropyridine type I.

1,3-Cycloalkanediones II, which are suitable precursors for preparation of bicyclic or polycyclic condensed heterocycles, respectively, are an important group of  1,3-dicarbonyl compounds. But in the literature, there is described only utilization of enolizable [6-9] lower 1,3-cycloalkanediones so far, mainly 1,3-cyclohexanedione II (k=2) in the Hantzsch pyridine synthesis [10-13]. The subject of our study included reactivity of two higher cycloalkanediones – 1,3-cycloheptanedione II(k=3) and 1,3-cyclooctanedione II(k=4). It is known that  these  two compounds do not enolize [14] at common condition and  they exclusively exist in oxo-form in contrast to most of  1,3-dicarbonyl compounds. However, it is clear from reaction mechanism [15] of the Hantzsch synthesis that the ability of  1,3-dicarbonyl compound to create enol or enolate anion respectively is an important presumption for success in this reaction.


Results and Discussion

 

In the first step we have been prepared enamines III a, b [16] as enol equivalents.

1,3-cycloalkanedione IIa or IIb was mixed in boiling benzene (reflux) at presence of catalytic amount of p-toluenesulfonic acid (PTSA) and at the same time gaseous ammonia was blown into the apparatus. Formed water was continuously removed by azeotropic distillation and enamine formed was gradually precipitated from the reaction mixture.  After cooling, the product was filtered off and recrystalized from mixture of ethyl acetate – ethanol (5:1).


We expected that if we use an enamine in the reaction (because Hantzsch pyridine synthesis was carried out as 3-component one: enamine of cycloalkanedione + aldehyde + β-dicarbonyl compound) we prepare unless asymmetric 1,4-dihydropyridines IV. In the contrary, if the Hantzsch synthesis is carried out as 4-component reaction (cycloalkanedione  +aldehyde + ammonia + β-dicarbonyl compound), it is also possible to expect creation of competitive symmetric 1,4-dihydropyridine V [17]. Their ratio depends on  the relative reactivity of individual components with active methylene group and their ability to form enolate.

In the second step, the prepared enamine III reacted with 2-fluorobenzaldehyde and acetylacetone (Z = COMe) or ethyl acetoacetate (Z = COOEt) respectively. The reaction was performed in boiling ethanol and triethylamine was used as a catalyst. After the reaction finished (disappearing of starting material under TLC control), the crude reaction mixture has been analysed using 1H NMR and then the solvent was evaporated and residue was chromatographed.


 Surprisingly we found out, that not only desirable product IV has been formed in all four reactions but also respective 1,4-dihydropyridine V as by-product.

 

Structure of all prepared derivatives of 1,4-dihydropyridines was confirmed by spectral methods 1H NMR, 13C NMR, IR and MS, respectively.

 

References

 

    1.    Rose, U.  Arzneim.-Forsch.  41, 199 (1991).

     2.    Safak, C.; Erdemli, I.; Sunal, R.  Arzneim. -Forsch. 43, 1052 (1993).

     3.    Oehldrich, J.; Cook, J. M.  J. Org. Chem. 42, 889 (1977).

     4.    Wolfbeis, O. S.; Junek, H.  Z. Naturforsch. ,B: Anorg. Chem. ,Org. Chem. 30 B, 249 (1975).

     5.    Troschütz, R.; Lückel, A.  Arch. Pharm. 324, 73 (1991).

     6.    Yogev, A.; Mazur, Y.  J. Org. Chem. 32, 2162 (1967).

     7.    Cyr, N.; Reeves, L. W.  Can. J. Chem. 43, 3057 (1965).

     8.    Noack, W.-E.  Theoret. Chim. Acta 53, 101 (1979).

     9.    Grens, E.; Grinvalde, A.; Vanags, G.  Zh. Prikl. Spektrosk. 6, 226 (1967).

   10.    Rose, U.  Pharm. Acta Helv. 65, 178 (1990).

   11.    Rose, U.  Arch. Pharm. 323, 281 (1990).

   12.    Abou-Gharbia, M.  Heterocycles 24, 1347 (1986).

   13.    Greenhill, J. V.; Moten, M. A.; Hanke, R.; Breitmaier, E.  J. Chem. Res. Synop. 66 (1981).

   14.    Schank, K.; Eistert, B.  Chem. Ber. 99, 1414 (1966).

   15.    Clayden, J.; Greeves, N.; Warren, S.; Wothers, P.  Organic chemistry, New York (by Oxford University Press), 1191 (2001).

   16.    Dammertz, W.; Reimann, E.  Arch. Pharm. 310, 172 (1977).

   17.    Ilavsky, D.; Milata, V. Collect. Czech. Chem. Commun.  61, 1233 (1996).