A novel approach to polysubstituted 3-aryl-2(1 H )-pyridinones

α -Benzotriazolylalkyl ketone 9 , easily prepared from α -chloroacetophenone and benzotriazole, react readily with arylacetamides 7 and aldehydes 8 to give single regioisomers of polysubstituted 3-aryl-2(1 H )-pyridinones 10 in moderate to good yields


Results and Discussion
Arylacetamides 7 are readily available from the corresponding arylacetyl chlorides and ammonia or primary amines according to a known procedure. 18α-Benzotriazolylalkyl ketone 9 was prepared by reacting α-chloroacetophenone with benzotriazole in refluxing toluene for 72 hours. 19Subsequent one-pot reaction of 7, 8, and 9 in refluxing n-butanol in the presence of potassium t-butoxide led to 3,4,6-triaryl-2(1H)-pyridinones 10 in yields of 48-74% (Table 1).The suggested reaction mechanism is shown in Scheme 3. Aldehydes 8 and αbenzotriazolylalkyl ketone 9 generated a,b-unsaturated ketones 11, which were isolated recently in our group and utilized for heterocyclizations with 1,2-dinucleophiles. 20In the present case, intermediates 11 were formed in situ under basic conditions and subsequently reacted with arylacetamides 7 to produce polysubstituted pyridinones 10.Compared to previous routes, which use selenium as an oxidant, or use strong basic conditions 12 , our present route employs easily accessible starting materials, a one-step reaction, and a simple work-up procedure and affords reasonable yields.The benzotriazole moiety both stabilizes the anion formed and promotes the aromatization of the heterocycle on the elimination step, thus further demonstrating the utility of benzotriazole in organic synthesis.
Two isomeric products 10 and 14 could have arisen from two possible pathways A or B as shown in Scheme 3.However, pathway A, which includes Michael addition of the anion of arylacetamide 7 to the unsaturated ketone 11 to give thermodynamically more stable intermediate 12, is more favorable.This opens the route to regiospecific pyridone ring annulation, and indeed only products of type 10 were isolated, although traces of 14a were detected from the NMR spectra of 10a.
Products 10a, 10e and 10g were identified by comparing the melting points with those published for the authentic compounds.The structures of novel compounds 10b-d, 10f were established by both spectroscopic and elemental analysis or HRMS, and confirmed by comparisons of their the NMR spectra with those of the known compounds 10a, 10e and 10g.The NMR spectra of 10 show a singlet in the region 6.60-7.04ppmand a broad signal in the region 11.90-13.43ppmwhich can be assigned to the proton at C(5) and the NH proton, respectively.
Definitive proof of structure was provided by the X-ray of the trifluoroacetate of 10h.(Figure 1) This is the first X-ray study of a 3,4,6-trisubstituted 2(1H)-pyridinone.Interestingly, the phenyl group in position 3 is out of conjugation with both pyridone ring, and 4 and 6 (hetero)aryl substituents.Perpendicular position of the 3-phenyl to the plane of the pyridone ring could influence the selectivity of their binding to receptors, such as GABA-A. 8In summary, [1+2+3] annulation reactions of arylacetamides 7, aldehydes 8 and αbenzotriazolylalkyl ketone 9 under basic conditions provide an efficient one-pot method for the regioselective preparation of 3,4,6-triaryl-2(1H)-pyridinones in good yields.

Experimental Section
General Procedures.Melting points were determined using a Bristoline hot-stage microscope and are uncorrected. 1H spectra were recorded at 300 MHz in CDCl 3 , except for compound 10d, which was done in CDCl 3 containing 5% (v/v) of TFA, and for compounds 10e-g, which were done in DMSO-d 6 . 13C NMR spectra were recorded at 75 MHz in the same solvents.Elemental analyses were performed on a Carlo Erba-1106 instrument.

General procedure for the preparation of 3-aryl-2(1H)-pyridinones 10a-h.
A mixture of the corresponding a-benzotriazolylalkyl ketone 9 (2 mmol), arylacetamide 7 (2 mmol), aldehyde 8 (2 mmol), and potassium tert-butoxide (0.45g, 4 mmol) in n-butanol (20 mL) was stirred under reflux for 16 h.On cooling, 4 N aqueous HCl solution was added to the reaction mixture until neutralization, and the precipitated crude product was collected by filtration, washed consecutively with water, methanol, and ether, and then air dried.Recrystallization from methanol/ethanol gave 10a-h as white or pale yellow solids from trifluoroacetic acid/methanol.