A high yielding oxidation method for the preparation of substituted 2,3-dihydro-4-pyridones from 4-piperidones

Abstract


Introduction
We recently reported on the total synthesis of the marine alkaloid cylindricine C (8) using a conjugate addition-dipolar cycloaddition cascade of 9-triisopropylsilanyloxy-non-1-en-5-one oxime (1) with 2,3-bis(phenylsulfonyl)-1,3-butadiene (2) as the key strategic element. 1 The cascade sequence proceeds by an initial conjugate addition of the oxime onto the activated diene followed by a proton transfer to create a transient nitrone that then undergoes a 1,3-dipolar cycloaddition with the tethered vinyl sulfone. 2 The resulting cycloadduct 3 was eventually converted into cylindricine C (8) by: (1) a reductive-cyclization cascade to set the BC-ring skeleton (i.e.4→5), (2) a base-induced cyclization to construct the tricyclic core (i.e.5→6), and (3) an oxidation-conjugate addition of the n-hexyl side chain (i.e.6→8) as indicated in Scheme 1.During the course of this study we came to realize that the oxidation of 4-piperidone 6 to the corresponding 2,3-dihydro-4-pyridone 7 was not a trivial transformation.A variety of standard oxidizing agents such as IBX, CAN and PhSeCl/NaIO 4 were examined but all failed to produce the dihydropyridone required for the subsequent conjugate addition step.We did have some limited success with the oxidation of 4-piperidone 9 when Polonovski conditions were utilized.Thus, the reaction of 9 with mCPBA, trifluoroacetic anhydride and triethyl amine in CH 2 Cl 2 brought about an overall oxidation.However, the product isolated in 90% yield corresponded to the undesired enamine 10.Most interestingly, when mercuric acetate was used as the oxidant, 3 the isomeric 2,3-dihydro-4-pyridone 11 was formed in 95% yield and no signs of 10 could be detected in the crude reaction mixture.Since 2,3-dihydro-4-pyridones are important synthetic intermediates, 4 we became interested in developing a method for their synthesis by oxidizing the related 4-piperidone system.The presence of the vinylogous amide in the six-membered azaheterocycle facilitates the introduction of other substituents onto the piperidine ring in a regio and stereocontrolled manner. 5Due to A 1,3 strain, 6 the C 2 group of the dihydropyridone 13 is forced into a pseudoaxial position providing a conformational bias in the molecule.This effect allows for control of the stereoselectivity of 1,2-and 1,4-addition to the enone moiety, C 3 enolate alkylation, Luche reduction of the C 4 carbonyl and intramolecular radical cyclization. 7,8The C 5 position can also be halogenated using NBS and a subsequent palladium-mediated coupling provides various 5substituted derivatives (Scheme 3). 9 A widely used method for the synthesis of the dihydropyridone system involves the reaction of carbon nucleophiles with various 1acylpyridinium salts (12). 4,10Because of the abundance of piperidine-containing natural products, 11 this method has been extensively utilized by Comins and coworkers for the asymmetric synthesis of many quinolizidine, indolizidine and perhydroquinoline alkaloids. 7nother approach that has been occasionally employed for the preparation of 2,3-dihydro-4pyridones consists of an oxidation of the related 4-piperidone system (i.e., 14→13). 12-Piperidones are readily available from the Dieckmann cyclization of aminodicarboxylate esters or by the condensation of carbonyl compounds with ammonia via a Mannich reaction. 13,14One general problem associated with this method is that the oxidation only works well when an electron withdrawing group is attached to the nitrogen atom.In addition, the reaction frequently leads to a mixture of 2,3-dihydro-4-pyridone isomers.Oxidation of N-acylated 4-piperidones are typically effected by using PhSeCl/H 2 O 2 , Saegusa or IBX methods (carbonyl directed dehydrative protocols). 12In contrast, the few reported examples of oxidation of N-alkyl substituted 4-piperidones almost always involve the use of a peracid induced Polonovski reaction 15 and generally results in meager yields of the corresponding vinylogous amide.Thus, a high yielding oxidation method for the preparation of substituted 2,3-dihydro-4-pyridones from 4-piperidones would be an advance in the area of heterocyclic synthesis.

Results and Discussion
The ubiquity and utility of the dihydropyridone system coupled with the difficulties that are associated with the oxidation of N-alkyl substituted 4-piperidones suggested a more detailed investigation.The earlier success of the mercuric acetate oxidation of piperidines by Leonard and coworkers 3 led us to test the utility of this oxidizing agent with various 4-piperidones.Scheme 4 outlines several 2,3-dihydro-4-pyridones that were prepared in good yield from the corresponding N-alkyl 4-piperidone precursor using mercuric acetate conditions.It should be noted that only the more substituted dihydropyridone (i.e., 18 and 20) was obtained from the oxidation thereby indicating a distinct preference for the formation of the thermodynamically most stable product.
We then conducted a brief exploration of the synthetic utility of the reaction to create the skeletal framework of various alkaloids.Reaction of the known bromide 22 with 1,4-dioxa-8azaspiro [4.5]decane (23) in the presence of K 2 CO 3 followed by a subsequent hydrolysis of the ketal provided 4-piperidone 24 in 87% yield.Mercuric acetate oxidation of 24 gave 25 in 88% yield.Treatment of 25 with 10% H 2 SO 4 at 90 °C induced initial enamide protonation and this was followed by a Pictet-Spengler cyclization.A subsequent mercuric acetate oxidation of the cyclized 4-piperidone intermediate afforded dihydropyridone 26 in 79% yield for the two-step sequence (Scheme 5).Of interest is the fact that only the more heavily substituted enamide 26 was formed in the final oxidation step.

(74%)
In summary, we have demonstrated that N-alkyl substituted 4-piperidones readily undergo oxidation in high yield upon reaction with mercuric acetate.The resulting 2,3-dihydro-4pyridones represent useful synthetic intermediates for a host of reactions.Studies concerning the application of the mercuric acetate oxidation to various 4-piperidones prepared by a conjugate addition/dipolar cycloaddition cascade of oximes with 2,3-bis(phenylsulfonyl)-1,3-butadiene are in progress and will be reported in due course.

Phenethyl-2,3-dihydro-1H-pyridin-4-one (21) was
21e mixture was heated to 80 o C for 2 h, and cooled to rt.The solution was transferred to a separatory funnel and partitioned between CH 2 Cl 2 and aqueous NH 4 Cl.The organic layer was extracted with ether, washed with aqueous NaHCO 3 , water, brine, dried over MgSO 4 , filtered, and then concentrated under reduced pressure.preparedusingthegeneralmercuric acetate conditions in 92% yield as a pale yellow oil; IR (CH 2 Cl 2 ) 3060, 1713, 1628, 1585, and 1180 cm -1 ; 1 H-NMR (300 MHz, CDCl 3 ) δ 2.43 (t, J = 7.9 Hz, 2H), 2.88 (t, J = 7.9 Hz, 2H), 3.41-3.48(m,4H),4.85(d,J = 7.5 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 7.16-7.The reaction mixture was transferred to a separatory funnel and partitioned between aqueous NaHCO 3 and ethyl acetate.The organic layer was washed twice with water, once with brine, dried over MgSO 4 and concentrated under reduced pressure.The crude residue was purified by flash silica chromatography to give 1.94 g (90%) of the intermediate acetal19as a ple yellow oil which was immediately dissolved in 79 mL of 2 N HCl in AcOH and then subjected to an acid hydrolysis.A solution of the above acetal in 2N HCl in AcOH was heated to 90 o C for 16 h.The reaction mixture was cooled to rt, brought to pH 8.0 with dilute NaOH, and extracted twice with toluene.The combined organic layer was washed with water, brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure.The crude residue was purified by flash silica gel chromatography to give 1.1 g (66%) of piperidone 24 as a colorless oil: IR (CH 2 Cl 2 ) 2926, 2359, Cl 2 .The combined organic layer was washed with water, brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure.The crude residue was purified by flash silica gel chromatography to give 10 mg (91%) of the intermediate quinolinone which was obtained as a pale yellow oil and was immediately subjected to the following reaction conditions.To a round bottom flask charged with the above compound was added 6.7 mL of water/ethanol (2:1), 12 mg (0.04 mmol) of mercuric acetate, and 15 mg (0.04 mmol) of EDTA.The mixture was heated to 80 o C for 2 h, cooled to rt and partitioned between aqueous NH 4 Cl and CH 2 Cl 2 .The organic layer was extracted, washed with aqueous NaHCO 3 , water, brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure.To a solution of 45 mg (0.18 mmol) of 1-[2-(1H-indol-3-yl)-ethyl]-2,3-dihydro-1H-pyridin-4-one21(29) in 3 mL of 20% H 2 SO 4 was added 1 mL of water and the mixture was heated to 90 o C for 12 h.The reaction mixture was cooled to rt, brought to pH 8.0 with dilute NaOH, and extracted twice with CH 2 Cl 2 .