Microwave-Assisted Synthesis of Chiral Nopinane-Annelated Pyridines by Condensation of Pinocarvone Oxime with Enamines Promoted by FeCl3 and CuCl2

Abstract Reaction of pinocarvone oxime with enamines and FeCl3 or CuCl2 resulted in annulation of nopinane carbon frame with pyridine and regioselective formation of chiral nopinane-annelated pyridines in 20–39% yields. Chemical structure of the pyridine derivatives were proved by precise NMR study. GRAPHICAL ABSTRACT


INTRODUCTION
Pyridine nucleus is one of the most important simple azaheterocycles, forming a great variety of biologically active molecules. Chiral pyridine derivatives are of special interest as ligands for coordination chemistry. [1] Natural monoterpene pinane-type hydrocarbons are among the most available primary sources of chirality for enantioselective syntheses, so pinane-type derivatives are of special interest for chiral auxiliary design, especially for syntheses of ligands used in chiral complexes of transition metals. Chiral ligands whose molecules contain both pyridine moiety and pinane carbon frame are prospective chiral auxiliaries. [2] There are a lot of different synthetic methods for construction of pyridine derivatives, some of them being used for building chiral hybrids containing pyridine and pinane frames: Krö hnke pyridine synthesis, [3][4][5] Friedländer quinoline synthesis, [6] Michael addition of the enolate and subsequent cyclization, [7] Michael addition of the 1,3-dicarbonyl compound to a,b-unsaturated oximes, and subsequent cyclization. [8] The use of a,b-unsaturated oximes for preparation of substituted pyridines is very convenient because the substrate molecule (a,b-unsaturated oximes) contains nitrogen atom, which is transformed to the pyridine nitrogen, so there is no need to use an additional reagent as a source of nitrogen in the pyridine synthesis.
Condensation of a,b-unsaturated oximes with enamines is known, [9] but the method described was successfully applied only to quite simple pyridines and is useless for syntheses of complex molecules because of the rather drastic conditions. Now we report a new method for designing chiral pyridine-pinane hybrides by condensation of pinocarvone oxime with enamines.

RESULTS AND DISCUSSION
Pinocarvone oxime seems to be the most available stable nitrogen-containing derivative of the pinane series and is the most accessible pinane-type a,b-unsaturated oxime, which is easily synthesized by two-step, one-pot preparation involving nitrosochlorination-dehydrochlorination of natural occurring a-pinene. [10] We tested condensation of pinocarvone oxime with enamines under wide range of the reaction conditions. The reaction was found to be catalyzed by a number of Lewis acids (FeCl 3 Á 6H 2 O, AlCl 3 , BF 3 Á OEt 2 , CuCl 2 Á 2H 2 O) and does not take place without a catalyst or in the presence of compounds such as Al(O-i-Pr) 3 . The best results (degree of the starting material conversion, isolation yields) were obtained when FeCl 3 Á 6H 2 O was used to promote condensation. Although anhydrous FeCl 3 also catalyzes the reaction, FeCl 3 Á 6H 2 O provides greater yields. Different solvents can be used (benzene, toluene, xylenes, pyridine, morpholine, dimethylformamide [DMF]), but in our hands the best results were achieved when the reaction was carried out without a solvent. The condensation requires heating up to 120-130 C, and microwave irradiation is the best choice to afford moderate yield over a period of 10-30 min, whereas ordinary heating requires a longer time to provide full conversion of the starting material, resulting in poor yields of the desired products.
The condensation technique is quite simple: a mixture of starting material (pinocarvone oxime and appropriate enamine 1:2 mol=mol) and FeCl 3 Á 6H 2 O (5-10 mol%) was heated at vigorous stirring in a sealed vessel for a certain period of time. After cooling to room temperature the mixture was treated with aqueous ammonia, and the reaction products were extracted with an organic solvent followed by column chromatography of the crude product to afford pure fused pyridines. All the pinane-pyridine derivatives synthesized are yellowish viscous oils or solids that are stable at ambient conditions. Precise analysis of 1 H and 13 C NMR spectra (long-range proton-proton and proton-carbon couplings) of the substituted derivatives 9, 10, 11, and 13 prove the following scheme of the condensation (Scheme 1), providing the C-1 enamine carbon to become a-carbon of the fused pyridine (tetrahydroquinoline) moiety.
The condensation seems to be a multistage process, with the precise role of catalyst being unclear. The catalyst (FeCl 3 , AlCl 3 , BF 3 Á OEt 2 , CuCl 2 ) is capable of forming complexes both with substrate (a,b-unsaturated oxime) and reagents (emanine) as well as with all the intermediates having donor heteroatomic functions. Probably the catalyst activates the substrate by complexation, because in absence of an enamine, self-condensation of a,b-unsaturated oxime occurs in the presence of FeCl 3 , resulted in a tar-like product.
The yields of the desired products are not high (Scheme 2), probably due to (a) limited stability of the starting material under the reaction conditions and (b) the fused pyridines formed are not inert under the reaction conditions and can act as substrates for further condensation. In certain cases the next step condensation product can be isolated, as it was shown for the pair oxime 1-enamine 14. Thus, when the most active catalyst was used (FeCl 3 Á 6H 2 O), double condensation C 2 -symmetric product 15 was isolated, whereas less active catalyst (CuCl 2 Á 2H 2 O) provided isolation of the primary condensation product 16.
In spite of moderate yields, the condensation seems to be a short and very convenient way to a variety of pinane-pyridine hybrids including previously published molecules. Thus, compounds 7 and 8 were prepared earlier by three-step syntheses from pinocarvone oxime, [11] whereas compounds 15 and 16 were synthesized by four-and six-step procedures correspondingly from pinocarvone. [12] EXPERIMENTAL All the solvents used were freshly distilled. (þ)-Pinocarvone (E)-oxime with mp 124 C (from light petroleum) (lit. [13] mp 132-134 C from hexane for a sample with unknown optical purity) and ½a 23 D þ 14 (c 0.85, CHCl 3 ) were prepared according to nitrosochlorination-dehydrochlorination [13,14] by addition of a solution of NOCl in CH 2 Cl 2 to (À)-a-pinene (W290203, Kosher) followed by treatment with Et 3 N. [10] Enamines 2, [15] 3, [15] 5, [16] 12, [16] and 14 [17] were prepared according to the published method by heating the corresponding ketones with morpholine in benzene under azeotropic distillation. Enamine 4 was prepared from propanal, morpholine, and anhydrous K 2 CO 3 at cooling as described in Ref. [18] 3-Aminocrotononitrile (diacetonitrile) 6 was prepared by treatment of acetonitrile with Na. [19] Microwave-assisted syntheses were carried out in a single-mode microwave reactor Discover TM System S-Class (CEM corp., USA) using a special 35-ml reaction vessel.
Merck silica gel 60 (0.063-0.100 mm) was used for preparative column chromatography. Analytical thin-layer chromatography (TLC) was carried out on a ready-touse plates (SiO 2 on Al foil). Visualization of components was achieved by sprinkling the plates with visualization solutions followed by heating to 100-150 C. The visualization solutions were (a) FeCl 3 Á 6H 2 O (10 g) þ 95% aq. EtOH (100 mL), (b)  NMR spectra were recorded at 25-28 C for solutions (c 20-40 mg=mL) on a Bruker DRX-500 spectrometer (500.13 MHz for 1 H, 125.75 MHz for 13 C) locked to the deuterium resonance of the solvent. The chemical shifts were calculated relative to the solvent signals (CDCl 3 ) used as the internal standard: d C 76.90 ppm and d H 7.24 ppm. Signal assignment was made using J modulated 13 C NMR spectra (proton-noise-decoupling, the opposite phases for the signals of the atoms with the odd and even numbers of the attached protons, tuning to the constant J ¼ 135 Hz) and 2D NMR spectra: (1) homonuclear 1 HÀ 1 H correlation, (2) heteronuclear 13 CÀ 1 H correlation at the direct spin-spin coupling constants (J ¼ 135 Hz), and (3) heteronuclear 13 CÀ 1 H correlation at the long-range spin-spin coupling constants (J ¼ 10 Hz). Carbon-proton spin-spin coupling constants were taken from protoncoupled 13 C NMR spectra.
Infrared (IR) spectra were recorded on a Bruker Tensor 27 spectrophotometer for solutions in KBr (c 0.25%). Ultraviolet (UV) spectra were recorded on an Agilent 8453 instrument. Optical rotation was measured with a PolAAr 3005 polarimeter at 589 nm and are expressed in deg Á cm 3 Á g À1 Á dm À1 and c is expressed in g=100 cm 3 . Melting points were determined by differential scanning calorimetry using a Netzsch STA 409 instrument. Mass spectra were obtained on a Termo electron DFS mass spectrometer (electron impact ionization, EI, 70 eV).

CONCLUSION
In conclusion, a new method for syntheses of pinane-fused pyridine derivatives was developed involving easily available pinocarvone oxime as starting material in the condensation reaction under transition-metal ion catalysis with microwave promotion. The method seems to be reasonable choice as compared to known methods because of its simplicity and the possibility of one-step preparation of certain fused pyridines.

FUNDING
The research was supported in part by the Russian Foundation for Basic Research (Grant Nos. 10-03-00346-a and 12-03-31078-young-a) and Grant No. 11.G34.31.0033 of the Government of the Russian Federation, designed to support research projects implemented by leading scientists at Russian institutions of higher learning.

SUPPLEMENTAL MATERIAL
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