Palladium-Catalyzed Direct C–H Arylation of Cyclic Enaminones with Aryl Iodides

Abstract

A ligand-free method for the Pd-catalyzed direct arylation of cyclic enaminones using aryl iodides was developed. This method can be applied to a wide range of cyclic enaminones and aryl iodides with excellent C5-regioselectivity. Using widely available aryl iodides, the generality of this transformation provides easy access to a variety of 3-arylpiperidine structural motifs.

Introduction

Cyclic enaminones, also known as 2,3-dihydropyrid-4(1H)-ones, have displayed a distinctive reactivity profile, including notably a strong innate nucleophilicity.¹ As piperidine surrogates, these non-aromatic substrates have been exploited as versatile synthetic intermediates in the syntheses of various heterocycles and heterocyclic natural products.² As our laboratory continues to investigate the pharmaceutical applications of phenanthropiperidine alkaloids, the syntheses of these natural products and analogs entail a regioselective C5-arylation of cyclic enaminones as a key step.³ Our strategy has been employing direct C–H arylation reactions because of their convenience and efficiency.

Direct C–H arylation chemistry has been extensively studied over the years due to the ubiquity of heterocycle-aryl linkages in pharmaceuticals.⁴ Our earlier syntheses have demonstrated that the regioselective C5-arylation of cyclic enaminones can be achieved through convenient and high yielding C–H arylation protocols via oxidative Pd catalysis (Scheme 1.1).⁵ In these protocols, aryl metal precursors were used (i.e. aryl boronic acids,^5a silanes,^5b and trifluoroborates^5c). Issues of limited commercial availability or high cost led us to explore the widely available aryl iodides as alternative reagents (Scheme 1.2).⁶

Scheme 1. Direct Arylation of Cyclic Enaminones.

Among the possible C–H activation mechanisms,⁷ our past study suggested that an electrophilic palladation pathway was more likely involved in reactions with the nucleophilic enaminones (Figure 1, top).^1a However, a carbopalladation process is also feasible and would lead to C6-arylation as the double bond in the non-aromatic enaminone scaffold could be a Heck-donor (Figure 1, bottom).^7c,7d Therefore, the regioselectivity of the coupling reaction presented another challenge. Herein, we disclose the development of a C5 regioselective direct C–H arylation of cyclic enaminones using aryl iodides.

Figure 1.

Postulated competing pathways for direct C–H arylation.

Results and Discussion

We initiated our study by examining a collection of C–H arylation conditions (catalysts, additives, reagent stoichiometry, and reaction time)⁸ and then proceeded with the Jeffery conditions (a combination of a Pd^II catalyst, a tetraalkylammonium salt, and an inorganic base)⁹ for the optimization studies shown in Table 1. As anticipated, in addition to the desired C5-arylated 3a, C6-arylated 4a was observed as well. A survey of seven solvents (entries 1–7) revealed that DMSO favored the formation of 3a via the presumed electrophilic palladation pathway (e.g. 50% in DMSO, entry 7 vs. 10% in dioxane, entry 2), whereas toluene (entry 1) significantly increased the formation of 4a. Indeed, DMSO provided the highest yield and the best regioselectivity (entry 7). The choice of the base was also proven imperative (entries 8–15). NaHCO₃ (entry 7) and Na₂CO₃ (entry 9) were more effective in facilitating the deprotonation process than NaOAc (entry 8). Addition of pivalic acid (PivOH) with Na₂CO₃ did not improve the yield (entry 10). The selection of base cations also showed that the sodium cation had beneficial effects on direct arylation (entries 11–13). Unsurprisingly, strong bases as NaOH (entry 14) or NaOtBu (entry 15) decomposed the enaminones. Thus, the originally chosen NaHCO₃ provided the best outcome (50%, entry 7). Next, the reaction temperature was tuned from 20 °C to 140 °C in 30-degree intervals (entries 16–19). We found that 80 °C was the optimal temperature to activate the transformation without decomposing the heat-sensitive enaminones. Moreover, several tetraalkylammonium salts were assessed as phase-transfer agents in order to enhance yields and selectivities (entries 20–22).⁹ The absence of Bu₄NBr indeed resulted in a lower yield of 3a and a reduced regioselectivity (entry 20). Interestingly, Bu₄NCl (entry 21) provided a better regioselectivity than Bu₄NI (entry 22) or Bu₄NBr (entry 7). Lastly, the ligand effect was investigated. Phosphine ligands (i.e. PPh₃, P(OPh)₃ and P(C₆F₅)₃), regardless of their electronic properties, were detrimental to catalysis (entries 23–25). Amino acids (i.e. Boc-L-alanine and Boc-L-phenylalanine), supposedly coordinating to the Pd center through weak ligation,¹⁰ showed no improvement in either yields or regioselectivity (entries 26–27).

Table 1. Initial Optimization of the Direct C–H Arylation of Cyclic Enaminones^a.

entry	ligand	additive	base	temp (°C)	solvent	3a (%)b	4a (%)b
1	—	Bu4NBr	NaHCO3	80	toluene	14	18
2	—	Bu4NBr	NaHCO3	80	dioxane	10	12
3	—	Bu4NBr	NaHCO3	80	tBuOH	8	12
4	—	Bu4NBr	NaHCO3	80	NMP	15	7
5	—	Bu4NBr	NaHCO3	80	DMF	29	7
6	—	Bu4NBr	NaHCO3	80	DMA	22	8
7	—	Bu4NBr	NaHCO3	80	DMSO	50	6
8	—	Bu4NBr	NaOAc	80	DMSO	36	5
9	—	Bu4NBr	Na2CO3	80	DMSO	49	8
10c	—	Bu4NBr	Na2CO3	80	DMSO	51	8
11	—	Bu4NBr	Li2CO3	80	DMSO	29	3
12	—	Bu4NBr	K2CO3	80	DMSO	16	0
13	—	Bu4NBr	Cs2CO3	80	DMSO	0	0
14	—	Bu4NBr	NaOH	80	DMSO	0	0
15	—	Bu4NBr	NaOtBu	80	DMSO	0	0
16	—	Bu4NBr	NaHCO3	20	DMSO	8	2
17	—	Bu4NBr	NaHCO3	50	DMSO	31	3
18	—	Bu4NBr	NaHCO3	110	DMSO	46	9
19	—	Bu4NBr	NaHCO3	140	DMSO	35	7
20	—	—	NaHCO3	80	DMSO	40	12
21	—	Bu4NCl	NaHCO3	80	DMSO	49	3
22	—	Bu4NI	NaHCO3	80	DMSO	35	16
23	PPh3	Bu4NCl	NaHCO3	80	DMSO	0	0
24	P(OPh)3	Bu4NCl	NaHCO3	80	DMSO	0	0
25	P(C6F5)3	Bu4NCl	NaHCO3	80	DMSO	0	0
26d	Boc-Ala-OH	Bu4NCl	NaHCO3	80	DMSO	52	6
27d	Boc-Phe-OH	Bu4NCl	NaHCO3	80	DMSO	45	4

^a1a (0.2 M), 2a (1.5 equiv), Pd(OAc)₂ (20 mol %), ligand (40 mol %), additive (1.0 equiv), base (3.0 equiv) in DMSO (1 mL). (p-Tol = para-tolyl)

^bNMR yields with Ph₃SiMe (1.0 equiv) as the internal standard.

^cWith PivOH (40 mol %).

^d2a (3.0 equiv), Bu₄NCl (0.5 equiv) and NaHCO₃ (1.0 equiv).

We also examined eight silver salts as additives (Table 2). Silver salts are often used to irreversibly abstract halide anions from Pd complexes thus rendering them more electrophilic and preventing the formation of mostly inactive PdI₂.¹¹ Indeed, the regioselectivity was greatly enhanced in the presence of a silver salt (entries 1–8). We found that AgCl not only increased the yield of 3a, but also promoted exclusive reaction at the C5-position (entry 6). Additional extensive fine-tuning⁸ of reagent stoichiometry and reaction time furnished the desired C5-arylated 3a in 72% with Bu₄NCl (0.5 equiv) and NaHCO₃ (1.0 equiv) in DMSO (0.5 mL) (entry 9).

Table 2. Silver Effect on the Regioselectivity of the Direct C–H Arylation of Cyclic Enaminones^a.

entry	Ag salt	3a (%)b	4a (%)b
1	AgTFA	33	<1
2	AgF2	14	0
3	AgNO3	32	0
4	AgOAc	30	<1
5	Ag2CO3	30	<1
6	AgCl	65	0
7c	Ag2O + benzoic acid	30	0
8c,d	Ag2O + PivOH	49	3
9e	AgCl	75 (72f)	<1

^a1a (0.2 M), 2a (3.0 equiv), Pd(OAc)₂ (20 mol %), Bu₄NCl (1.0 equiv), NaHCO₃ (3.0 equiv), silver salt (1.2 equiv) in DMSO (1 mL). (p-Tol = para-tolyl)

^bNMR yields with Ph₃SiMe (1.0 equiv) as the internal standard.

^cAg₂O (0.75 equiv), acid (1.5 equiv), no NaHCO₃.

^dNo Bu₄NCl.

^eAgCl (1.2 equiv), Bu₄NCl (0.5 equiv), NaHCO₃ (1.0 equiv) in DMSO (0.5 mL). (See Table S2 in the Supporting Information for more detail.)

^fIsolated yield.

Next we explored the scope of aryl iodides in this reaction using the optimized conditions (Table 3) and found that the electronic properties of the aryl iodides affected reaction yields significantly. Good yields were generally obtained with electron-rich aryl iodides (3a–3l). Electron-poor aryl iodides afforded slightly lowered yields (3m–3p). Reactions of aryl iodides with strongly electron-withdrawing substituents, e.g. NO₂(3o) and CF₃(3p), resulted in low yields. Steric hindrance, as expected, impeded the effectiveness of the cross coupling. For instance, compared to the 4-tolyl derivative (3a), 2-tolyl iodide afforded a lower yield (3b) with 14% recovered 1a. In addition, arylation of bifunctional 4-chlorophenyliodide (2n) proceeded exclusively at the iodine terminus with the chlorine terminus intact, which may be subjected to sequential cross-coupling reactions.¹² It is worth mentioning that phenyl bromide was tested under the optimized conditions and afforded an inferior yield (21% with 32% recovered 1a) compared to phenyl iodide, which afforded 3d in 68%. Neither 4-chlorotoluene nor phenyl triflate functioned as arylating reagents to afford the desired product.

Table 3. Scope of Aryl Iodides for the Direct C–H Arylation^a.

^a1a (0.2 M), 2 (3.0 equiv), Pd(OAc)₂ (20 mol %), Bu₄NCl (0.5 equiv), NaHCO₃ (3.0 equiv), AgCl (1.2 equiv) in DMSO (0.5 mL), 24 h. Isolated yields with full consumption of 1a, unless otherwise noted.

^b14% recovered 1a.

Given the high coupling efficiency of electron-rich aryl iodides, a series of cyclic enaminones was subjected to the optimized conditions with 4-iodoanisole (2f, Table 4). Consistent with our previous results,^1a,5 electron-rich, monocyclic and bicyclic enaminones were all compatible with the optimized conditions (3q–3v). Compared to N-benzylenaminone 3q, N-phenylenaminone 3r was formed in a decreased yield probably due to its attenuated nucleophilicity. Notably, these mildly basic conditions did not compromise the stereochemical integrity of the epimerizable enaminone 3v. In contrast, no reaction took place on either the N-unprotected enaminone 1w or the E-enaminone 1x to form products 3w or 3x.^1a,5 Electron-deficient enaminones also failed to furnish desired 5-arylated products 3y or 3z.

Table 4. Scope of Cyclic Enaminones for the Direct C–H Arylation^a.

^a1 (0.2 M), 2f (3.0 equiv), Pd(OAc)₂ (20 mol %), Bu₄NCl (0.5 equiv), NaHCO₃ (3.0 equiv), AgCl (1.2 equiv) in DMSO (0.5 mL), 24 h. Isolated yields with full consumption of 1, unless otherwise noted.

^b60% recovered 1w.

^c65% recovered 1x.

^d15% recovered 1y.

^e27% recovered 1z.

Mechanistically, the aforementioned electrophilic palladation pathway (Figure 1) for direct arylation can account for the observed C5-regioselectivity, the silver salt effect, the solvent dependency, and the substituent effects. Presumably, AgCl abstracts the iodide from the Pd oxidative adduct (i.e. Ar–Pd–I) to generate a cationic [Ar–Pd]⁺ complex, whose electrophilicity matches the innate C5-nucleophilicity of enaminones to yield C5-arylated enaminones. This unique C5-regioselectivity is enhanced by DMSO because the cationic [Ar–Pd]⁺ species should be stabilized by this highly polar and coordinating solvent. In addition, the [Ar–Pd]⁺ species should also be stabilized by electron-donating substituents, which would lead to less catalyst degradation and subsequently higher yields (e.g. 80% of 3h vs. 32% of 3o). It is worth noting that a concerted-metalation-deprotonation (CMD) mechanism cannot be excluded at this time. However, the lack of reactivity of the electron-deficient enaminones 1y and 1z indicates a low possibility for this process, which often works well on electron-deficient substrates.¹³ In addition, a Pd^II/Pd^IV catalytic cycle, albeit not ruled out, is also less likely because (1) more than one catalytic turnover was observed in the absence of silver salts (e.g.Table 1, entry 7, TON = 2.5), suggesting that silver salts did not serve to regenerate the Pd catalyst;¹⁴(2) our initial optimization demonstrated that other Pd⁰ catalysts (e.g. Pd(dba)₂ or Pd₂(dba)₃) would catalyze C5-arylation as well, albeit in low yields (8–11%).⁸ Presumably, the ligands in these Pd⁰ conditions tempered the electrophilicity of the Pd^II center after oxidative addition, hence resulting in the observed low yields.

Conclusion

We have developed a straightforward method for the regioselective C–H arylation of cyclic enaminones with aryl iodides. In spite of showing reduced but nevertheless good yields compared to our earlier arylation protocols, the new method reported herein utilizes aryl iodides with broader commercial availability. This transformation tolerates a wide range of substrates and presents an alternative approach to synthesize 3-arylpiperidine derivatives.

Experimental section

General information

All reactions were carried out in clear 1-dram vials under air. Vials were used without drying. Palladium(II) acetate, aryl iodides, all other chemicals and solvents were purchased and were directly used without further purification. Cyclic enaminones (1a,^1a 1q–1r,^3d,15 1s,^5b and 1t–1w ^3d,15) were prepared according to the reported procedures and enaminone 1x is commercially available. Flash column chromatography was carried out on silica gel (230–400 mesh). TLC was conducted on 250 micron, F₂₅₄ silica gel plates. ¹H NMR spectra were recorded at 400 MHz and ¹³C NMR spectra at 100 MHz with complete proton decoupling. Chemical shifts are reported as ppm relative to chloroform (CHCl₃: 7.26 ppm for ¹H, 77.16 ppm for ¹³C). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz) and integration. IR spectra of solids were obtained by dissolving the sample in CH₂Cl₂ and letting the solvent evaporate on a NaCl plate. High-resolution mass spectrometry was performed on an ESI-TOF instrument. Melting points are uncorrected.

Representative procedure for direct C–H arylation of cyclic enaminones with aryl iodides

In a clear 1-dram vial, the cyclic enaminone (0.1 mmol), aryl iodide (0.3 mmol, 3.0 equiv), Pd(OAc)₂ (4.5 mg, 0.02 mmol, 20 mol %), Bu₄NCl (13.9 mg, 0.05 mmol, 0.5 equiv), NaHCO₃ (8.4 mg, 0.1 mmol, 1.0 equiv), and AgCl (17.2 mg, 0.12 mmol, 1.2 equiv) were mixed in DMSO (0.5 mL). The reaction vessel was then capped and stirred at 80 °C for 24 h, and then cooled to room temperature. The mixture was filtered through a pad of Celite (washed with EtOAc). The filtrate was concentrated under reduced pressure and purified by flash column chromatography.

1-Benzyl-2-(4-methoxyphenyl)-5-(p-tolyl)-2,3-dihydropyridin-4(1H)-one (3a)

Compound 3a was prepared by the general procedure described above and purified by flash column chromatography (30% EtOAc in hexanes) on silica gel to provide 27.3 mg (72%) as an orange wax. Analytical data are consistent with those from our previous report.^5a

1-Benzyl-2-(4-methoxyphenyl)-6-(p-tolyl)-2,3-dihydropyridin-4(1H)-one (4a)

Compound 4a was a side product during the optimization study and purified by flash column chromatography (25% EtOAc in hexanes) on silica gel as a yellow wax. ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.20 (m, 9H overlapping with CHCl₃), 7.15 (d, J = 6.8 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.17 (s, 1H), 4.76 (d, J = 15.7 Hz, 1H), 4.61 (dd, J = 7.3, 4.0 Hz, 1H), 3.99 (d, J = 15.7 Hz, 1H), 3.81 (s, 3H), 2.97 (dd, J = 16.5, 7.4 Hz, 1H), 2.61 (dd, J = 16.7, 3.9 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.1, 164.9, 159.4, 140.0, 137.8, 133.6, 131.3, 129.6, 129.0, 128.0, 128.0, 127.8, 127.2, 114.4, 102.8, 59.4, 55.5, 53.9, 42.6, 21.5; FTIR (NaCl, cm^-1) 3054, 2987, 1639, 1598, 1513, 1442, 1179, 1032, 896; HRMS (ESI+) m/e calculated for [M+H]⁺ C₂₆H₂₆NO₂: 384.1963, found 384.1969.

1-Benzyl-2-(4-methoxyphenyl)-5-(o-tolyl)-2,3-dihydropyridin-4(1H)-one (3b)

Compound 3b was prepared by the general procedure described above and purified by flash column chromatography (25% EtOAc in hexanes) on silica gel to provide 16.9 mg (43%) as a yellow solid (mp 139–142 °C). ¹H NMR (400 MHz, CDCl₃) δ 7.32–7.22 (m, 4H overlapping with CHCl₃), 7.18–7.03 (m, 8H), 6.83 (d, J = 8.6 Hz, 2H), 4.48 (t, J = 7.6 Hz, 1H), 4.27 (d, J = 15.1 Hz, 1H), 4.10 (d, J = 15.1 Hz, 1H), 3.75 (s, 3H), 2.85 (dd, J = 16.3, 6.7 Hz, 1H), 2.76 (dd, J = 16.3, 8.7 Hz, 1H), 2.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.7, 159.7, 154.0, 138.2, 136.2, 136.0, 130.6, 130.2, 129.1, 128.6, 128.5, 128.3, 127.9, 127.2, 125.8, 114.5, 112.6, 60.7, 57.3, 55.5, 44.4, 20.7; FTIR (NaCl, cm^-1) 3054, 2987, 1638, 1596, 1551, 1422, 1157, 1029, 896; HRMS (ESI+) m/e calculated for [M+Na]⁺ C₂₆H₂₅NO₂Na: 406.1783, found 406.1779.

1-Benzyl-2-(4-methoxyphenyl)-5-(m-tolyl)-2,3-dihydropyridin-4(1H)-one (3c)

Compound 3c was prepared by the general procedure described above and purified by flash column chromatography (30% EtOAc in hexanes) on silica gel to provide 27.2 mg (72%) as a yellow wax. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.34 (td, J = 18.5, 15.9, 9.5 Hz, 4H), 7.25–7.14 (m, 6H), 7.07–6.99 (m, 1H), 6.89 (d, J = 8.5 Hz, 2H), 4.52 (t, J = 7.5 Hz, 1H), 4.41 (d, J = 15.1 Hz, 1H), 4.21 (d, J = 15.1 Hz, 1H), 3.82 (s, 3H), 2.95 (dd, J = 16.2, 6.8 Hz, 1H), 2.82 (dd, J = 16.2, 8.3 Hz, 1H), 2.37 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 159.7, 153.3, 137.8, 136.1, 130.6, 129.1, 128.6, 128.6, 128.5, 128.3, 128.3, 127.8, 126.7, 124.8, 114.5, 111.4, 60.4, 57.5, 55.5, 44.6, 21.7; FTIR (NaCl, cm^-1) 3054, 2987, 1639, 1598, 1513, 1422, 1179, 1035, 896; HRMS (ESI+) m/e calculated for [M+Na]⁺ C₂₆H₂₅NO₂Na: 406.1783, found 406.1779.

1-Benzyl-2-(4-methoxyphenyl)-5-phenyl-2,3-dihydropyridin-4(1H)-one (3d)

Compound 3d was prepared by the general procedure described above and purified by flash column chromatography (30% EtOAc in hexanes) on silica gel to provide 24.8 mg (68%) as a yellow oil. Analytical data are consistent with those from our previous report.^5a

1-Benzyl-5-(4-(tert-butyl)phenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3e)

Compound 3e was prepared by the general procedure described above and purified by flash column chromatography (25% EtOAc in hexanes) on silica gel to provide 27.9 mg (66%) as a yellow wax. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.43–7.29 (m, 7H), 7.24–7.14 (m, 4H), 6.88 (d, J = 8.7 Hz, 2H), 4.52 (t, J = 7.5 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H), 4.20 (d, J = 15.1 Hz, 1H), 3.82 (s, 3H), 2.96 (dd, J = 16.2, 6.8 Hz, 1H), 2.83 (dd, J = 16.2, 8.4 Hz, 1H), 1.33 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 159.7, 153.1, 148.7, 136.1, 133.2, 130.7, 129.1, 128.5, 128.3, 127.9, 127.4, 125.3, 114.5, 111.3, 60.5, 57.5, 55.5, 44.6, 34.5, 31.5; FTIR (NaCl, cm^-1) 3054, 2986, 1637, 1598, 1513, 1422, 1376, 1358, 1306, 1179, 1130, 1034, 896, 837; HRMS (ESI+) m/e calculated for [M+Na]⁺ C₂₉H₃₁NO₂Na: 448.2252, found 448.2259.

1-Benzyl-2,5-bis(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3f)

Compound 3f was prepared by the general procedure described above and purified by flash column chromatography (50% EtOAc in hexanes) on silica gel to provide 29.2 mg (74%) as a yellow oil. Analytical data are consistent with those from our previous report.^5a

1-Benzyl-5-(3-methoxyphenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3g)

Compound 3g was prepared by the general procedure described above and purified by flash column chromatography (35% EtOAc in hexanes) on silica gel to provide 31.2 mg (79%) as a red oil. Analytical data are consistent with those from our previous report.^5a

1-Benzyl-2-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3h)

Compound 3h was prepared by the general procedure described above and purified by flash column chromatography (50% EtOAc in hexanes) on silica gel to provide 36.5 mg (80%) as a yellow solid (mp 125–128 °C). ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.39–7.31 (m, 3H), 7.23–7.14 (m, 4H), 6.89 (d, J = 8.6 Hz, 2H), 6.67 (s, 2H), 4.52 (t, J = 7.5 Hz, 1H), 4.42 (d, J = 15.1 Hz, 1H), 4.22 (d, J = 15.1 Hz, 1H), 3.87 (s, 6H), 3.83 (s, 3H), 3.81 (s, 3H), 2.95 (dd, J = 16.2, 6.8 Hz, 1H), 2.81 (dd, J = 16.2, 8.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 159.8, 153.1, 136.5, 136.0, 131.9, 130.5, 129.1, 128.5, 128.5, 128.4, 127.9, 114.6, 111.0, 105.2, 61.0, 60.4, 57.5, 56.3, 55.5, 44.6; FTIR (NaCl, cm^-1) 3054, 2987, 2840, 1639, 1598, 1583, 1512, 1422, 1357, 1327, 1129, 1034, 1005, 896; HRMS (ESI+) m/e calculated for [M+H]⁺ C₂₈H₃₀NO₅: 460.2118, found 460.2126.

1-Benzyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3i)

Compound 3i was prepared by the general procedure described above and purified by flash column chromatography (40% EtOAc in hexanes) on silica gel to provide 35.4 mg (83%) as an orange wax. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (s, 1H), 7.39–7.30 (m, 3H), 7.20–7.14 (m, 4H), 6.98–6.81 (m, 5H), 4.50 (dd, J = 8.4, 6.8 Hz, 1H), 4.37 (d, J = 15.1 Hz, 1H), 4.24 (s, 4H), 4.17 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.92 (dd, J = 16.2, 6.7 Hz, 1H), 2.80 (dd, J = 16.2, 8.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 159.7, 152.9, 143.3, 142.0, 136.1, 130.6, 129.7, 129.1, 128.5, 128.3, 127.8, 121.1, 117.0, 116.7, 114.5, 111.0, 108.8, 64.5, 60.5, 57.4, 55.5, 44.6; FTIR (NaCl, cm^-1) 3155, 2935, 1635, 1597, 1583, 1511, 1459, 1442, 1377, 1357, 1315, 1298, 1282, 1250, 1178, 1127, 1071, 1036, 834; HRMS (ESI+) m/e calculated for [M+Na]⁺ C₂₇H₂₅NO₄Na: 450.1681, found 450.1684.

1-Benzyl-2-(4-methoxyphenyl)-5-(4-morpholinophenyl)-2,3-dihydropyridin-4(1H)-one (3j)

Compound 3j was prepared by the general procedure described above and purified by flash column chromatography (70% EtOAc in hexanes) on silica gel to provide 33.9 mg (75%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.38– 7.30 (m, 5H), 7.23–7.12 (m, 4H), 6.92–6.86 (m, 4H), 4.51 (t, J = 7.6 Hz, 1H), 4.38 (d, J = 15.1 Hz, 1H), 4.18 (d, J = 15.1 Hz, 1H), 3.86 (t, J = 4.6 Hz, 4H), 3.81 (s, 3H), 3.14 (t, J = 4.0 Hz, 4H), 2.93 (dd, J = 16.3, 6.6 Hz, 1H), 2.82 (dd, J = 16.2, 8.7 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 188.3, 159.7, 152.7, 149.6, 136.2, 130.7, 129.1, 128.6, 128.6, 128.3, 127.8, 116.0, 114.5, 114.5, 111.3, 67.1, 60.6, 57.4, 55.4, 49.8, 44.7; FTIR (NaCl, cm^-1) 3155, 2967, 2901, 2839, 1794, 1634, 1595, 1514, 1452, 1380, 1307, 1231, 1177, 1121, 1035, 907; HRMS (ESI+) m/e calculated for [M+H]⁺ C₂₉H₃₁N₂O₃: 455.2329, found 455.2324.

1-Benzyl-2-(4-methoxyphenyl)-5-(naphthalen-1-yl)-2,3-dihydropyridin-4(1H)-one (3k)

Compound 3k was prepared by the general procedure described above and purified by flash column chromatography (40% EtOAc in hexanes) on silica gel to provide 33.3 mg (80%) as a red wax. ¹H NMR (400 MHz, CDCl₃) δ 7.89–7.75 (m, 3H), 7.50–7.28 (m, 10H), 7.19 (d, J = 6.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 4.66 (t, J = 7.7 Hz, 1H), 4.38 (d, J = 15.1 Hz, 1H), 4.23 (d, J = 15.1 Hz, 1H), 3.86 (s, 3H), 3.06 (dd, J = 16.3, 6.5 Hz, 1H), 2.97 (dd, J = 16.2, 8.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 188.3, 159.8, 154.8, 136.1, 134.3, 134.0, 133.2, 130.5, 129.1, 128.6, 128.6, 128.4, 128.0, 128.0, 127.9, 127.7, 126.3, 125.7, 125.7, 114.6, 111.1, 60.7, 57.4, 55.6, 44.5; FTIR (NaCl, cm^-1) 3155, 3035, 2936, 2840, 1794, 1637, 1599, 1513, 1464, 1442, 1388, 1376, 1359, 1306, 1253, 1178, 1137, 1096, 1035, 834, 796; HRMS (ESI+) m/e calculated for [M+Na]⁺ C₂₉H₂₅NO₂Na: 442.1783, found 442.1783.

5-([1,1′-Biphenyl]-4-yl)-1-benzyl-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3l)

Compound 3l was prepared by the general procedure described above and purified by flash column chromatography (30% EtOAc in hexanes) on silica gel to provide 32.2 mg (73%) as a yellow wax. ¹H NMR (400 MHz, CDCl₃) δ 7.68–7.51 (m, 7H), 7.46–7.31 (m, 6H), 7.23–7.18 (m, 4H), 6.90 (d, J = 8.6 Hz, 2H), 4.55 (t, J = 7.5 Hz, 1H), 4.44 (d, J = 15.1 Hz, 1H), 4.23 (d, J = 15.1 Hz, 1H), 3.82 (s, 3H), 2.99 (dd, J = 16.2, 6.8 Hz, 1H), 2.86 (dd, J = 16.2, 8.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 159.8, 153.1, 141.3, 138.6, 136.0, 135.3, 130.5, 129.1, 128.8, 128.5, 128.5, 128.4, 128.0, 127.9, 127.1, 127.1, 114.6, 110.9, 60.5, 57.6, 55.5, 44.6; FTIR (NaCl, cm^-1) 3054, 2087, 1638, 1597, 1513, 1488, 1421, 1357, 1179, 1126, 1035, 896; HRMS (ESI+) m/e calculated for [M+Na]⁺ C₃₁H₂₇NO₂Na: 468.1939, found 468.1937.

1-Benzyl-5-(4-(ethoxycarbonyl)phenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3m)

Compound 3m was prepared by the general procedure described above and purified by flash column chromatography (30% EtOAc in hexanes) on silica gel to provide 21.9 mg (50%) as a yellow wax. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.37 (q, J = 6.1 Hz, 3H), 7.22–7.14 (m, 4H), 6.88 (d, J = 8.6 Hz, 2H), 4.55 (t, J = 7.3 Hz, 1H), 4.46 (d, J = 15.1 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.25 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.98 (dd, J = 16.2, 6.9 Hz, 1H), 2.82 (dd, J = 16.2, 7.8 Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ ¹³C 187.7, 166.9, 159.9, 153.5, 141.1, 135.7, 130.2, 129.7, 129.2, 128.6, 128.4, 127.89, 127.4, 126.9, 114.6, 110.0, 60.8, 60.3, 57.8, 55.4, 44.5, 14.5; FTIR (NaCl, cm^-1) 3054, 2987, 1707, 1642, 1597, 1513, 1422, 1368, 1180, 1127, 1107, 1034, 896; HRMS (ESI+) m/e calculated for [M+Na]⁺ C₂₈H₂₇NO₄Na: 464.1838, found 464.1832.

1-Benzyl-5-(4-chlorophenyl)-2-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3n)

Compound 3n was prepared by the general procedure described above and purified by flash column chromatography (25% EtOAc in hexanes) on silica gel to provide 20.3 mg (51%) as a yellow wax. Analytical data are consistent with those from our previous report.^5a

1-Benzyl-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-2,3-dihydropyridin-4(1H)-one (3o)

Compound 3o was prepared by the general procedure described above and purified by flash column chromatography (30% EtOAc in hexanes) on silica gel to provide 13.0 mg (32%) as a bright yellow solid (mp 98–100 °C). Analytical data are consistent with those from our previous report.^5a

1-Benzyl-2-(4-methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)-2,3-dihydropyridin-4(1H)-one (3p)

Compound 3p was prepared by the general procedure described above and purified by flash column chromatography (25% EtOAc in hexanes) on silica gel to provide 12.8 mg (30%) as a yellow wax. Analytical data are consistent with those from our previous report.^5a

1-Benzyl-5-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3q)

Compound 3q was prepared by the general procedure described above and purified by flash column chromatography (70% EtOAc in hexanes) on silica gel to provide 22.6 mg (78%) as a yellow oil. Analytical data are consistent with those from our previous report.^5a

5-(4-Methoxyphenyl)-1-phenyl-2,3-dihydropyridin-4(1H)-one (3r)

Compound 3r was prepared by the general procedure described above and purified by flash column chromatography (50% EtOAc in hexanes) on silica gel to provide 14.1 mg (50%) as an orange solid (mp 129–132 °C). Analytical data are consistent with those from our previous report.^5a

1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-5-(4-methoxyphenyl)-2-phenyl-2,3-dihydropyridin-4(1H)-one (3s)

Compound 3s was prepared by the general procedure described above and purified by flash column chromatography (30% EtOAc in hexanes) on silica gel to provide 20.3 mg (45%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 1H), 7.39–7.28 (m, 7H), 6.87 (d, J = 8.7 Hz, 2H), 4.67 (t, J = 7.4 Hz, 1H), 3.80 (s, 3H), 3.64 (t, J = 5.6 Hz, 2H), 3.37 (dt, J = 14.6, 7.4 Hz, 1H), 3.23 (dt, J = 13.6, 6.4 Hz, 1H), 3.01 (dd, J = 16.2, 6.7 Hz, 1H), 2.82 (dd, J = 16.2, 8.0 Hz, 1H), 1.72 (p, J = 6.3 Hz, 2H), 0.85 (s, 9H), 0.01 (s, 3H), -0.01 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.6, 157.9, 153.3, 138.9, 129.2, 128.9, 128.9, 128.4, 127.0, 113.8, 110.8, 61.4, 59.4, 55.5, 50.5, 44.6, 31.7, 26.0, 18.3, -5.3; FTIR (NaCl, cm^-1) 3054, 2987, 2930, 2857, 1635, 1596, 1512, 1422, 1178, 1156, 1101, 1036, 896, 836; HRMS (ESI+) m/e calculated for [M+Na]⁺ C₂₇H₃₇NO₃SiNa: 474.2440, found 474.2440.

3-(4-Methoxyphenyl)-7,8,9,9a-tetrahydro-1H-quinolizin-2(6H)-one (3t)

Compound 3t was prepared by the general procedure described above and purified by flash column chromatography (50% EtOAc in hexanes) on silica gel to provide 16.0 mg (63%) as a yellow oil. Analytical data are consistent with those from our previous report.^5a

(4aR,8aR)-3-(4-Methoxyphenyl)-1-methyl-4a,5,6,7,8,8a-hexahydroquinolin-4(1H)-one (3u)

Compound 3u was prepared by the general procedure described above and purified by flash column chromatography (30% EtOAc in hexanes) on silica gel to provide 12.9 mg (48%) as a yellow wax. Analytical data are consistent with those from our previous report.^5a

(4aS,8aR)-3-(4-Methoxyphenyl)-1-methyl-4a,5,6,7,8,8a-hexahydroquinolin-4(1H)-one (3v)

Compound 3v was prepared by the general procedure described above and purified by flash column chromatography (50% EtOAc in hexanes) on silica gel to provide 16.3 mg (60%) as a yellow wax. Analytical data are consistent with those from our previous report.^5a