The S ynthesis of D iverse A nnulated P yridines with 6-M embered F unctionalized S aturated C ycles for M edical C hemistry R esearch

The article describes a set of pyridines annulated with functionalized 6-membered saturated rings, which are attractive building blocks for the synthesis of diversified compound libraries in medical chemistry. A certain array of compounds includes pyridines with condensed cyclohexane, piperidine and tetrahydropyran cycles containing keto-, amino-, carboxylic groups, as well as fluorinated fragments. The synthesis of the compounds using the procedure previously developed by us via CuCl 2 -catalyzed condensation of propargylamine with ketones was performed. The limits of application of this reaction were further expanded and determined in this work compared to our previous results. Condensed pyridines, which proved problematic or impossible to obtain by this method, were synthesized using other synthetic pathways. Thus, the study offers a number of new building blocks for use in drug discovery

Due to such a wide spectrum of the biological activity demonstrated, chemists need convenient and cost-effective methods for the synthesis of diverse functionalized PASCs in multigram and/or even semi-industrial scales.In this research, we demonstrate our strategy for solving this problem and propose a synthetic strategy for producing a set of bicyclic building blocks containing pyridine and an annelated saturated core with various substituents and functional groups.According to the development of "magic methyl" and "magic fluorine" concepts, along with classical functions, we included compounds bearing methylmethylene (2), dimethylmethylene (3) and difluoromethylene (4) moieties in our short-list.Isomeric conformationally restricted ketones 6a -d, carboxylic acids 7a -d, PASCs with exocyclic amine function 8a -d and those featuring endocyclic one 9a -d were also treated as utility building blocks for modern combinatorial chemistry and drug discovery (Figure 2).
Reported approaches towards pyridines annulated with 6-membered saturated cycles include: (A) the partial reduction of the corresponding aromatic compounds, (B) the construction of the saturated 6-membered ring and (C) the construction of the pyridine ring.Viable routes to implement the approaches are illustrated by a retrosynthetic analysis of compound 9c (Figure 3).
Approach C can also be illustrated by the intermolecular Diels-Alder reaction with an inverse electron demand [6], intermolecular oxidative cyclization [7,8] or [4+2]-cyclization.Examples of [4+2]-cyclization include reactions catalyzed by gold [9] and ruthenium [10 -13].Recently, our research group proposed a simple and scalable method via the condensation catalyzed by available and cheap CuCl 2 [14] (Figure 4).Thanks to our research, this approach has become costeffective and, along with good scalability and diversity, very promising for obtaining such compounds.
In this light, we aimed to extend and determine the scope of the method and perform the synthesis of the set of diverse PASCs.In addition, in some cases of the method, we proposed other approaches for the synthesis of the target molecules.

■ Results and discussion
In our previous work [9], we reported on the synthesis of the parent core 1, ketones 6a and 6b, carboxylic acid 7b, amines 8a, 9a, 9b and dihydropyranopyridine 10b.The scope of the method was successfully expanded to the synthesis of pyridines fused with saturated rings bearing CHMe-, CMe 2 -, CF 2 -, CHOH-moieties.Propargylamine (11) was condensed with ketones 12 -16 in the presence of anhydrous CuCl 2 to obtain the desired products (including compounds 3 and 4 previously unknown).
Although alcohol 5 was reported previously, the yield was neither good (e.g., 28 %) [15] nor even reported.Our approach works much better -a one-step scalable procedure provides 58 % yield of 5. We also attempted to oxidize alcohol 5 to obtain known [16,17] ketone 6b via the Dess-Martin oxidation.However, the yields were low (10 -15 %), so this way needed further optimizations.Notably, ketone 6b can be involved in selfcondensation reactions, and therefore, it should be stored in the freezer.
Ketone 6c still remains a challenge for synthetic chemists (our attempts were unsuccessful as well), while more than 20 different reactions for the synthesis of ketone 6d were reported, even in a kilogram scale [18].
Previously, we obtained ethyl esters of carboxylic acids 7a and 7c as an inseparable mixture.The synthesis of 7c in 75 % via the Wolff-Kishner reduction was reported in 1974 [19].Carboxylic acids 7b and 7d [20] were also reported.The synthesis of the previously unknown 7a was carried out starting from ketone 6a.At the first stage, the ketone was transformed to the enol triflate 17, and the latter was further carbonylated with CO to form ester 18. Compound 18 was successfully reduced to saturated acid 19, the acidic hydrolysis of the latter led to the target acid 7a (Scheme 2).
Ketone 20 reacts with propargylamine yielding pyridine Boc-9a, as it was described in our previous work, and isomer Boc-9c were detected (Scheme 3, A).Therefore, the condensation of ketone 20 with propargylamine is not a suitable method for the synthesis of 9c.Multistep preparations of 9c were reported earlier [8,9].Alternatively, 1,7-naphtyridine partial reduction gave mixtures of isomers [7].Hereby, we proposed an alternative 4-step way starting from nitrile 21 (Scheme 3, B).
The scalable synthesis of amine 9d from pyridine 25 was performed through an elegant route based on the construction of the piperidine ring on the b-bond of pyridine in 2-fluoro-4-chloropyridine (25) (Scheme 4).In contrast to the procedures previously reported [21 -23], the proposed reaction sequence leads to a single isomer, consists of common organic procedures and uses available starting materials.

■ Conclusions
A representative set of pyridines annelated with 6-membered functionalized saturated rings has been synthesized.The scope of CuCl 2 -catalyzed condensation of propargylamine with ketones has been extended.Other synthetic methods have been proposed for pyridines that cannot be obtained using this procedure.A set of novel building blocks related to medical chemistry has been created for drug development.

■ Experimental part
All solvents were purified according to the standard procedures.Absolute ethanol and isopropanol were used.All starting materials were obtained from Enamine Ltd.Melting points were measured on an automated melting point system. 1 H and 13 C NMR spectra were measured on a Bruker Avance 500 spectrometer (at 500 MHz for 1 H and 126 MHz for 13 C nuclei) and a Varian Unity Plus 400 spectrometer (at 400 MHz for 1 H and 101 MHz for 13 C nuclei).Tetramethylsilane ( 1 H, 13 C) was used as an internal standard.Mass spectra were recorded on an Agilent 5890 Series II 5972 GCMS instrument (atmospheric pressure electrospray ionization (ESI)).

The general procedure for the synthesis of pyridines 2 -5 and 10c
Pyridines 2 -5 and 10c were obtained according to the procedure previously developed [9].
The procedure for the synthesis of 5,6,7,8tetrahydroquinoline-5-carboxylic acid hydrochloride (7a*HCl) To 6 L round-bottomed flask dried in the oven, 7,8-dihydroquinolin-5(6H)-one (6a) (147.2 g, 1 mol, 1.0 equiv) was added.The flask was sealed and purged with argon before the addition of CH 2 Cl 2 (2.8 L) and Et 3 N (208 mL, 1.5 mol, 1.5 equiv).The reaction mixture was cooled to 0°C, and trifluoromethanesulfonic anhydride (242 mL, 6.2 mmol, 1.5 equiv) was added dropwise under argon atmosphere before heating to 40°C and kept at this temperature while stirring for 24 h.Upon completion of the reaction, the solution was washed with water (2×20 mL), and the organic substances were passed through a hydrophobic frit, and concentrated under reduced pressure to give compound 17 quantitatively (~279 g) as a brown oil (85 -90 % purity), which was used in the next step without purification.
A solution of 17 (279 g, 1 mol) in DMF (2.2 L) was treated with methanol (1.1 L) and N,N-diisopropylethylamine (526 mL, 3 mol), and bubbled with argon for 30 min.The resulting mixture was treated with DPPF (4.5 g, 8 mmol) and palladium (II) acetate (1.8 g, 8 mmol).The resulting solution was bubbled with carbon monoxide for 30 min, and then stirred under a carbon monoxide balloon at 60 o C for 6 h.After that, the mixture was cooled to room temperature and diluted with ethyl acetate.The resulting mixture was washed with 1 M aqueous HCl, twice with water, once with the saturated aqueous sodium carbonate, dried over sodium sulfate and then concentrated under vacuum to yield 147.6 g of a residue (78 %, ~90 % purity) as a yellowish powder.The product was used in the next step without purification.
A solution of 18 (147.6g, 0.78 mol) in MeOH (2 L) was heated at 50 o C under atmospheric pressure and bubbled with H 2 for 2 h in the presence of 10 % Pd on charcoal (10 g).After completing the reaction, Pd/C was filtered off, and the residue was evaporated under reduced pressure.The yellowish powder (~149 g, ~90 % purity) obtained was used in the next step without purification.
The product 19 (95.6 g, 0.5 mol) was dissolved in the saturated solution of HCl in dioxane (1 L) and boiled until the end of the precipitate formation.Then the solid was filtered off and dried on air.The final product 7a was obtained as a white powder in 84 % yield as hydrochloride (89.The procedure for the synthesis of 1,7naphthyridin-8(7H)-one (23) 3-Methylpicolinonitrile (21) (23.62 g, 0.2 mol) and the Bredereck's reagent (69.6 g, 0.2 mmol) were dissolved in DMF (250 mL).The reaction mixture was heated at 75°C under argon for 72 h.After that, the solvent was removed in vacuo.Trituration with MTBE gave a brown oil 21 (~35 g, ~0.2 mol, a quantitative yield, ~85 % purity).Further all 35 g of the product was used without additional purification.
The oil from the previous step was dissolved in the saturated solution of HCl in dioxane (200 mL).The reaction mixture was warmed at 45 -50°C for 24 h.The reaction solution was filtered, and the filtrate was collected and dried.The light brown solid 23 (  The procedure for the synthesis of 8-chloro-1,7-naphthyridine (24 ) 1,7-Naphthyridin-8(7H)-one (23) (19.1 g, 0.15 mol) was dissolved in 200 mL of toluene.POCl 3 (31 g, 0.2 mol) and DIPEA (72 g, 4 mol) were added to the reaction mixture, and then it was

Figure 1 .
Figure 1.Examples of biologically active compounds containing a PASC moiety

Figure 2 .Figure 3 .
Figure 2. A representative set of PASC building blocks

Figure 4 . 2 Scheme 1 .Scheme 2 .
Figure 4.The known approaches for the synthesis of the pyridine ring of PASCs .