Synthesis and structure of cycloalkane‐ and norbornane‐condensed 6‐aryl‐1,2,4,5‐tetrahydropyridazinones

Abstract

Dedicated to Prof. Sándor Antus on the occasion of his 60 th birthday.The C=N double bond of certain cis-or trans-cycloalkane and diexo-or diendo-norbornane-condensed pyridazinones was reduced with NaBH 3 CN. The cis-or trans nature of the starting cycloalkane derivatives was always retained in the saturated products, with a high degree of diastereoselectivity: the hydrogen on the new stereocenter and the annelational hydrogen next to the carbonyl always exhibited the same steric orientation. The stereostructures were determined by means of nmr measurements and confirmed by molecular modelling. Numerous cycloalkane-condensed 4,5-dihydropyrid a z i n -3 ( 2H)-ones have recently been prepared [1-3] and dehydrogenated with SOCl 2 in benzene and with CuCl 2 in C H 3 CN [4,5] or reacted with Zn/HCl, which leads to a diastereoselective reductive ring contraction [6]. The selective reduction and ring transformation of pyridazinones and phthalazinones are carried out under similar conditions [7,8]. By cleavage of the N-N bond, the reduction of phthalazinones with BH 3 /THF affords α-s u b s t ituted 1,2-benzenedimethanamines [9]. The hydrogenation of pyridazinones with LiAlH 4 furnishes the partially reduced 1,4,5,6-tetrahydropyridazinones [10], which behave as nonsteroidal progesterone receptor ligands [11]. For saturation of the C=N bond in pyridazinones, sodium cyanoborohydride (NaBH 3 CN) was found to be a mild, simple and regioselective reducing agent; its application has been well documented and reviewed in detail [12]. In this way, the macrocyclic dilactam skeleton of peptidal antibiotics (e . g . glidobactin A) [13] and 1,2-diazetid-3-ones has been prepared [14].Our present investigation was focused on the saturation of cycloalkane-condensed pyridazinones by the application of NaBH 3 CN in an effort to attain diastereoselectivity. Results.For saturation of the double bond in the bicyclic c i s-or t r a n s-cyclohexane-and tricyclic, norbornane-condensed dihydropyridazinones 6 -1 0, 1 6 and 1 7, which are easily accessible v i a the reactions of c i s-or t r a n s-2 -p-t o l u o y l c ycloalkane-or d i e x o-and d i e n d o-n o r b o r n a n e c a r b o x y l i c acids [15] with hydrazine [1], NaBH 3 CN in MeOH solution was added in portions at 0 °C, followed by hydrochloric acid dropwise (Schemes 1 and 2). The mixtures were made slightly alkaline and extracted with C H 2 C l 2 and the products were purified by column chrom a t o g r a p h y. In all cases, only a single diastereomer could be isolated. The t r a n s dihydropyridazine 1 0 gave the saturated t r a n s product 1 5.For the diendo-norbornane-fused derivative 19, only a markedly poor (28%) yield was obtained, whereas all the other reactions resulted in the saturated derivatives in good to excellent yields (75-94%).