Photoredox-Catalyzed Giese Reactions: Decarboxylative Additions to Cyclic Vinylogous Amides and Esters

Abstract

An effective strategy has been developed for the photoredox-catalyzed decarboxylative addition of cyclic amino acids to both vinylogous amides and esters leading to uniquely substituted heterocycles. The additions take place exclusively trans to the substituent present on the dihydropyridone ring affording stereochemical control about the new carbon-carbon bond. These reactions are operationally simplistic and afford the desired products in good to excellent isolated yields.

1. Introduction

Reductive addition of carbon-centered radicals to electron-deficient olefins, known as the Giese reaction, has been utilized in a number of synthetic applications including total syntheses [1,2,3,4,5,6,7]. Visible-light photoredox-catalyzed Giese reactions have garnered a great deal of interest in recent years as a valuable method for the construction of carbon-carbon bonds in an atom-economical manner under relatively mild reaction conditions. Recent examples of carbon-centered radicals utilized in the Giese reaction have been generated via carboxylic acids [8,9,10], trifluoroborate salts [11,12], secondary and tertiary alcohols [13,14,15], organosilicates [16,17,18], alkyl halides [19], and via triplet enone diradicals [20]. Decarboxylative Giese reactions involving readily available amino acids have emerged as a powerful method for the construction of carbon-carbon bonds leading to the formation of molecules not previously accessible by other methods [8,9]. Reactions leading to increasing molecular complexity are extremely valuable synthetic tools and our interest in this area was inspired by the unique reactivity of cyclic vinylogous amides and esters of type 3 and 4 (Figure 1). It was envisioned that addition of carbon-centered radicals generated via a photocatalytic decarboxylation of amino acids would allow for the preparation of unprecedented and novel heterocyclic scaffolds 3 and 4. In this manuscript we document our investigations in this area.

2. Results and Discussion

Our investigations began by examining the reaction between dihydropyridone 5 [21] and amino acid 6 (Scheme 1). A high throughput screen of 24 photocatalysts was conducted employing potassium phosphate dibasic or potassium carbonate as bases and dimtheylformamide (DMF) or dimethylsulfoxide (DMSO) as solvents. The starting materials were dosed into pre-assembled vials containing a separate photocatalyst and base and were irradiated at 450 nm for 24 h. The samples were then analyzed by liquid chromatography mass spectrometry (LCMS). The first screen yielded two “hits” for the desired mass. The photocatalysts of interest were identified as (Ir[dF(CF₃)ppy]₂(dtbby))PF₆ [22] and 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) [23] employing potassium phosphate dibasic and DMF. These reactions were subsequently scaled up to 100 mg scale and purified by mass-directed HPLC. Interestingly, upon examining the nuclear magnetic resonance (NMR) of the isolated product it was found that the radical added exclusively trans to the phenyl group on the dihydropyridone. We speculate that the initially formed product 7 undergoes cyclization to aminal 8 during the mass-directed purification which employed aqueous trifluoroacetic acid (TFA) and acetonitrile. The observation that the radical approached trans to the phenyl group was further supported by molecular calculations which demonstrated that a cis approach is 3.8 kcal/mol higher in energy than the trans approach. This is perfectly in line with the fact that substituents on dihydropyridines bearing a carbamate prefer an axial orientation due to A^1,3 strain between an equatorial substituent and the carbamate. This is also in line with the fact that Grignard reagents favor the trans products when reacted with dihydropyridones of type 5. The resulting steric environment of the axial substituent leads to the radical approaching from the opposite face leading to the observed cis-isomer. Although the desired product was formed in the reaction, the isolated yield was <10% for the iridium photocatalyst and < 5% for the 4CzIPN catalyst. Reexamination of the crude reaction mixture revealed that at least two other major products had formed but were inseparable from one another. After a series of NMR experiments on the crude reaction mixture the structures were determined to be a 2:1 mixture of 2 + 2 dimers 9 and 10. It is believed that the initially formed radical generated from amino acid 6 is sufficiently stable or self-quenches and dimerization becomes the major pathway. We speculate that intermolecular photocycloaddition leading to compounds 9 and 10 occurs through energy transfer from the iridium catalyst upon light absorption. The reaction was repeated with several other primary, secondary and tertiary acyclic amino acids and similar results were obtained.

Our attention then turned to screening cyclic amino acids in order to probe whether these would have better reactivity and deliver the desired product in useful yields. The initial photocatalytic screen was performed employing dihydropyridone 5 and Boc L-proline 11 (Scheme 2). The same optimal conditions discovered above were found also in this screen and the desired product was formed in much higher apparent yield. The optimal conditions employed were to irradiate at 450 nm the dihydropyridone 5 in DMF in the presence of 1 mol% Ir[dF(CF₃)ppy]₂(dtbby) and 2 equiv of both K₂HPO₄ and Boc L-proline for 20 h. Under these conditions, the desired product 12 was obtained in 82% isolated yield and as a 1:1 inseparable mixture of diastereomers about the carbon where the radical was formed. There were only trace amounts of 2 + 2 dimers in the crude NMR and these were easily separable from the products In addition, the trans product was the exclusive product formed, there being no detectable amounts of the cis products formed in the reaction. The trans stereochemistry was further confirmed by NMR.

With these results in hand, the scope of the transformation was explored employing the optimized conditions. For example, an azetidine radical generated from Boc-protected amino acid 13 cleanly added to dihydropyridone 5 to give product 14 in 90% isolated yield and as an inseparable mixture of diastereomers. (

Table 1. Scope of amino acid additions to dihydropyridone 5.

Entry	Amino Acid	Product	Yield, dr
1			90%, 1:1
2			83%, 2.8:1
3			68%, 2.8:1
4			85%, 1:1
5			69%, 1:1
6			58%, 2:1
7			82%, 3:1

, entry 1). Interestingly, reaction with amino acid 15 provided the desired product with modest levels of diastereoselectivity (2.8:1) where the major product of 16 could be isolated by fractional crystallization of the mixture from EtOAc/hexane after purification by silica gel chromatography (Table 1, entry 2). In similar fashion, reaction of amino acid 17 with dihydropyridone 5 also provided a 2.8:1 mixture of diastereomeric products 18; however, these products could not be separated from one another by either silica gel or fractional crystallization (Table 1, entry 3). The morpholine and indoline amino acids 19 and 21 also added to dihydropyridone 5 providing the desired products 20 and 22 in 85% and 69% yields, respectively (Table 1, entries 4,5). In both cases, there were no observable levels of diastereoselectivety and a 1:1 mixture of products was obtained. The diastereomers of 20 were separable by silica gel chromatography; however, the diastereomers of 22 were inseparable. As an extension of these investigations, it was discovered that tetrahydropyran-2-carboxylic acid 23 could also be utilized leading to compound 24 in 58% yield and a separable 2:1 mixture of diastereomers (Table 1, entry 6). In addition, dihydrobenzofuran-2-carboxylic acid 25 underwent smooth decarboxylative radical formation and addition to dihydropyridone 5 to provide product 26 in 82% isolated yields and as a 3:1 separable mixture of diastereomers (Table 1, entry 7). The major diastereomer of compound 26 was subjected to a series of NMR experiments and density functional theory (DFT) calculations in order to determine the configuration of the 3 chiral centers of the major diastereomer. From these experiments it was determined that the major diastereomer 26a had the stereochemistry as depicted in Scheme 3.

Reaction of tetrahydrofuran-2-carboxylic acid 27 with dihyropyridone 5 under the standard conditions (Ir[dF(CF₃)ppy]₂(dtbby))PF₆ 1 mol%, 450 nm, K₂HPO₄ 2 equiv, 20 h) led to full conversion and afforded the expected product 28 as a separable 3:2 mixture of diasteremers and was isolated in 70% yield (Scheme 4). A complementary approach to this molecule involved the recently reported nickel-catalyzed addition of THF to enones involving an energy-transfer initiated catalysis involving triplet diradicals [20]. Irradiation at 450 nm of dihydropyridone 5 in the presence of 1 mol% (Ir[dF(CF₃)ppy]₂(dtbby))PF₆ in the presence of 5 mol% NiBr₂ glyme, 15 mol% 2,2′-bis(2-oxazoline (BiOx) in tetrahydrofuran (THF) resulted in 82% conversion after 24 h and afforded compound 28 in 70% isolated yield. Under these conditions, compound 28 was obtained as a 3:2 mixture of diastereomers which was identical to the decarboxylative process and was obtained in similar levels of diastereoselectivity.

We next turned our attention to the addition of these carbon-centered radicals to both 4-oxoquinolines 29 [24] and chromen-4-ones 30 to further broaden the scope of the transformation (Scheme 5). As revealed in

Table 2. Photocatalytic decarboxylative additions to 4-Oxoquinline 29 and chromenone 30.

Entry	Starting Material	Amino Acid	Product	Yield, dr
1	29	13		38%, 1:1
2	29	11		55%, 1:1
3	29	14		61%, 4:1
4	29	16		65%, 4:1
5	30	11		65%, 1:1
6	30	21		61%, 1:1
7	30	27		68%, 1:1
8	30	15		92%, 1:1

, reaction with amino acids 13 and 11 with 4-oxoquinoline 29 under the standard conditions provided products 31 and 32 as a 1:1 mixture of diastereomers in 38% and 55% isolated yields, respectively. The individual diastereomers of product 31 were separable whereas the diastereomers of product 32 could not be separated from one another. Reaction of compound 29 with amino acids 14 and 16 provided the desired products 33 and 34 in slightly higher yield. In each of these cases the observed diastereoselectivity increased to 4:1; however, these diastereomers were inseparable from one another. Reaction of chromenone 30 with the radicals generated from amino acids 11 and 21, was also successful providing the addition products 35 and 36 in good yields and as inseparable mixtures of diastereomers. In addition, the radical generated from tetrahydrofuran-2-carboxylic acid gave product 37 in 68% isolated yield where the individual diastereomers could be separated from each other. Finally, reaction of chromenone 30 with amino acid 15 afforded heterocycle 38 in 92% yield and as a 1:1 mixture of separable diastereomers.

3. Materials and Methods

All anhydrous solvents were supplied by Sigma Aldrich in Sureseal^® bottles and used without further purification. All commercially available chemicals were used as received. Reactions were monitored by ultra-performance liquid chromatography UPLC employing an Agilent Technologies 1290 Infinity II UPLC with a Waters Aquity UPLC DEH C18 column (1.7 mm, 2.1 × 100 mm, 0.4 mL/min, 40 ℃ solvent A 0.1% H₃PO₄/water: B MeCN, 90:10 to 10:90 A:B over 8 min). Silica gel chromatography was performed with a 24-gram pre-packaged cartridge on a Teledyne ISCO CombiFlash Rf using a gradient of 0–100% methyl tert-butyl ether (MTBE)/hexane. NMR spectra were obtained on a Bruker 500 MHz spectrometer. Elemental analysis was performed at Intertek Pharmaceutical Services. HMRS were obtained at Merck & Co., Inc., Kenilworth, NJ, USA.

Preparation of Trans-phenyl-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-oxo-6-phenylpiperidine-1-carboxylate (12). According the the general procedure, reaction of 200 mg (10.68 mmol) of dihydropyridone 5 with 294 mg (1.36 mmol) of N-Boc-L-proline 11 in the presence of 238 mg (1.36 mmol) of HK₂PO₄ and 10 mg (0.012 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 260 mg (82%) of compound 12 as a colorless oil and as inseparable 1:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.36 (m, 2H), 7.30–7.12 (m, 7H), 6.74 (d, 2H, J = 7.9 Hz), 5.73 and 5.61 (d, 1H, J = 6.4 and 6.6 Hz), 4.65–4.47 (m, 1.17H), 4.39–4.29 (m, 0.64H), 3.97 (m, 0.66H), 3.60–3.49 (m, 0.80H), 3.47–3.31 (m, 1H), 3.20 (br m, 0.30H), 2.85 (m, 1.3 H), 2.69–2.54 (m, 1.27H), 2.23 (m, 0.57H), 2.05–1.87 (m, 2.6H), 1.68 (m, 0.62H), 1.63–1.45 (m, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 206.6, 155.6, 155.2, 151.1, 143.5, 129.3, 129.1, 128.9, 128.8, 127.4, 127.2, 127.0, 125.5, 125.3, 125.2, 125.1, 121.8, 121.6, 121.5, 80.1, 79.5, 60.9, 56.5, 56.2, 55.5, 54.5, 53.7, 47.4, 47.2, 46.1, 46.0, 44.8, 41.0, 40.9, 39.7, 29.1, 29.0, 28.6, 28.4, 27.0, 23.3, 23.0. HRMS Calcd. For C₂₇H₃₃N₂O₅ [M = H}: 465.2389. Found: 465.2380.

Preparation of Trans-1-(tert-butoxycarbonyl)azetidin-2-yl)-4-oxo-6-phenylpiperidine-1-carboxylate (14). According the the general procedure, reaction of 160 mg (0.55 mmol) of dihydropyridone 5 with 220 mg (1.10 mmol) N-Boc-azetidine-2-carboxylic acid 13 in the presence of 190 mg (1.13 mmol) of HK₂PO₄ and 9.4 mg (8.4 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 220 mg (90%) of compound 14 as colorless oil and as an inseparable 1:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.42–7.27 (m, 7H), 7.19 (br m, 2H), 6.95 (br m, 1H), 5.78 (m, 1H), 5.04 (m, 0.5H), 4.93 (m, 0.5H), 4.60 (m, 0.5H), 4.38 (m, 0.5H), 3.91 (m, 1.5H), 3.75 (dt, 1.5H, J = 9.0 and 6.7 Hz), 3.42 (m, 0.5H), 2.99–2.81 (m, 2H), 2.72 (m, 0.5H), 2.54 (m, 1.5H), 1.94 (m, 1H), 1.51 and 1.49 (s, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 205.8 and 205.1, 157.8, 151.0, 142.1, 129.4, 129.3, 129.2, 129.0, 128.9, 127.4, 127.3, 125.6, 125.4, 125.3, 125.2, 121.6, 80.4, 64.9, 64.4, 56.4, 55.2, 54.5, 47.3, 45.8, 44.2, 39.4, 37.7, 28.5 and 28.4, 21.3, 20.0. HRMS Cacld. For C₂₆H₃₁N₂O₅ [M + H]: 451.2233. Found: 451.2239.

Preparation of Trans-1-(tert-butyl-1-phenyl-4-oxo-6-phenyl-[2,2’-bipiperidine]-1,1’dicarboxylate (16). According the the general procedure, reaction of 133 mg (0.45 mmol) of dihydropyridone 5 with 158 mg (0.91 mmol) N-Boc-pipecolic acid 15 in the presence of 208 mg (0.91 mmol) of HK₂PO₄ and 7.5 mg (6.7 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 183 mg (83%) of compound 16 as separable 2.8:1 mixture of diastereomers and rotamers: First Isomer to elute: colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 7.39 (m, 2H), 7.24 (m, 5H), 7.13 (m, 1H), 6.62 (br m, 2H), 6.66 and 5.52 (br m, 1H), 5.18 and 5.07 (br m, 1H), 4.42 (br m, 1H), 4.16 (br m, 1H), 3.99 (d, 1H, J = 12.4 Hz), 3.55–3.32 (br m, 1H), 2.89–2.55 (m, 2H), 1.74–1.48 (m, 15H);); ¹³C-NMR (CDCl₃, 125 MHz) δ 206.2, 158.9, 129.1, 129.0, 128.9, 127.4, 127.2, 125.5, 125.4, 125.0, 121.5, 121.4, 56.8, 53.6, 49.9, 45.5, 41.3, 40.7, 28.5, 28.1, 25.6, 24.8, 18.9. HRMS calcd for C₂₈H₃₄N₂O₅ [M + H]: 479.2546. Found: 479.2552. Second Isomer to elute: colorless solid; ¹H NMR (500 MHz, CDCl₃) δ 7.50 (m, 2H), 7.25 (m, 5H), 7.16 (m, 1H), 6.74 (br m, 2H), 5.66 (m, 1H), 5.11 (m, 1H), 4.70 (br m, 0.5H), 4.50 (br m, 0.5H), 4.21 (d, 0.5H, J = 12.7 Hz), 4.01 (d, 0.5H, J = 12.4 Hz), 3.69 (m, 0.5H), 3.43 (m, 0.5H), 2.89–2.54 (m, 4H), 1.94 (br m, 2H), 1.72–1.53 (m, 3H), 1.46 (s, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 204.3, 155.3, 145.3, 150.8, 129.3, 129.2, 129.0, 128.9, 127.6, 127.4, 125.7, 125.6, 125.0, 121.4, 80.9, 80.2, 56.4, 56.3, 54.8, 53.2, 49.8, 49.4, 45.4, 45.2, 40.6, 39.7, 39.6, 39.0, 28.5, 28.4, 28.2, 25.7, 25.3, 25.0, 24.7, 19.4, 19.3, 18.9. Anal. Calcd. For C₂₈H₃₄N₂O₅: C, 70.27; H, 7.16; N, 5.85. Found, C, 69.97; H, 6.99; N, 5.82.

Preparation of Trans-tert-butyl-4-oxo-1-(phenoxycarbonyl)-6-phenylpiperidin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (18). According the the general procedure, reaction of 164 mg (0.56 mmol) of dihydropyridone 5 with 310 mg (1.12 mmol) of N-Boc-tetrahydroquinoline-2-carboxylic acid 17 in the presence of 195 mg (1.12 mmol) of HK₂PO₄ and 13 mg (0.011 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 202 mg (68%) of compound 18 as colorless oil and an inseparable 2.8:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.40 (m, 12H), 6.75 and 6.88 (br m, 2H), 5.79 and 5.73 (d, 1H, J = 5.6 and 6.9 Hz), 5.11 and 4.84 (m, 1H), 4.64–4.57 (br m, 1H), 4.03 and 3.57 (m, 1H), 3.01–2.89 (m, 2H), 2.57–2.38 (m, 3H), 2.00 (m, 1H), 1.54 and 1.51 (s, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 206.1 and 204.6, 155.1 and 154.7, 151.2 and 150.9, 143.8 and 142.2, 137.1 and 136.3, 131.6, 129.4, 129.1, 128.9, 128.8, 128.4 and 128.3, 127.5 and 127.3, 126.2, 126.1, 125.9, 125.7, 125.2, 125.1, 124.8, 124.7, 121.6 and 121.4, 81.7 and 81.1, 57.0, 56.5, 55.5, 54.9, 45.7 and 45.0, 41.1, 39.3, 30.3, 28.4 and 28.3, 26.9, 26.2, 24.2. HRMS Calcd. For C₃₂H₃₅N₂O₅ [M + H]: 527.2546 Found: 527.2553.

Preparation of Trans-tert-butyl-4-oxo-1-(phenoxycarbonyl)-6-phenylpiperidin-2-yl)morpholine-4-carboxylate (20). According the the general procedure, reaction of 158 mg (0.539 mmol) of dihydropyridone 5 with 249 mg (1.08 mmol) of 4-Boc-3-morpholinecarboxylic acid 19 in the presence of 188 mg (1.08 mmol) of HK₂PO₄ and 9.1 mg (8.1 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 310 mg (65%) of compound 20 as a separable 1:1 mixture of diastereomers and rotamers in 85% combined yield. Isomer #1: colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.24 (m, 7H), 7.14 (m, 1H), 6.62 (br m, 2H), 5.65 and 5.51 (d, 1H, J = 6.8 and 7.2 Hz), 5.40–5.31 (m, 1H), 4.15–3.47 (m, 7H), 3.10–3.02 (m, 1H), 2.93–2.75 (m, 2H), 1.61 and 1.54 (m, 9H), 1.50 (m, 1H); ¹³C-NMR (CDCl₃, 125 MHz) δ 206.0, 205.0, 155.5, 150.9, 143.9, 129.3, 129.1, 129.0, 128.9, 127.6, 127.3, 125.7, 125.5, 125.1, 125.0, 121.8, 121.5, 80.9, 80.6, 67.5, 66.9, 66.6, 57.0, 56.2, 55.9, 53.9, 48.6, 45.5, 44.9, 41.1, 40.8, 39.3, 28.7, 28.5, 28.3, 28.1. HRMS Calcd. For C₂₇H₃₃N₂O₅ [M + H]: 480.2260. Found: 480.2257. Isomer #2: colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 7.39 (m, 2H), 7.28 (m, 5H), 7.16 (m, 1H), 6.87 (br m, 2H), 5.69 (m, 1H), 5.27 (m, 1H), 4.48 (d, 0.5H, J = 7.9 Hz), 4.30 (d, 0.5H, J = 8.2 Hz), 4.20 (d, 0.5H, J = 12.0 Hz), 4.13 (d, 0.5H, J = 12.0 Hz), 4.03 (m, 0.5H), 3.90 (m, 1H), 3.81 (d, 0.5H, J = 12.5 Hz), 3.64 (m, 1.7H), 3.50 (m, 1.3H), 3.33 (dd, 0.5H, J = 16.9 and 6.9 Hz), 3.09 (m, 0.5H), 3.00–2.69 (m, 3H), 2.60 (m, 0.5H), 1.51 (m, 1H), 1.48 (s, 9H). HRMS Calcd. For C₂₇H₃₃N₂O₅ [M + H]: 481.2339. Found: 481.2242.

Preparation of Trans-tert-butyl-4-oxo-1-(phenoxycarbonyl)-6-phenylpiperidine-2-yl)indoline-1-carboxylate (22). According the the general procedure, reaction of 166 mg (0.56 mmol) of pyridone 5 with 298 mg (1.13 mmol) N-Boc-indoline-2-carboxylic acid 21 in the presence of 197 mg (1.13 mmol) of HK₂PO₄ and 9.4 mg (8.4 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 201 mg (69%) of compound 22 as colorless oil and as an inseparable 1:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.49–6.70 (m, 15H), 5.91 and 5.82 (d, 1H, J = 7.5 and 6.5 Hz), 5.62 (br m, 0.5H), 5.45 (br m, 1H), 4.66 (m, 1H), 4.57 (m, 1H), 3.55 (dd, 1H, J = 16.5 and 10.1 Hz), 3.41 (dd, 0.5H, J = 16.0 and 8.3 Hz), 3.29 (dd, 1.2H, J = 16.8 and 7.4H), 2.99-2.90 (br m, 2.3H), 2.73 (br dd, 2.25H, J = 29.2 and 17.5 Hz), 2.49 (dd, 1.2H, J = 17.5 and 7.3 Hz), 2.23 (d, 1H, J = 17.8 Hz), 1.65 and 1.63 (s, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 206.4, 203.5, 153.5, 152.5, 151.2, 142.6, 142.5, 130.4, 129.6, 129.5, 129.3, 129.1, 128.9, 128.3, 127.7, 127.4, 125.6, 125.3, 125.1, 124.5, 123.8, 123.2, 121.7, 121.3, 82.0, 62.5, 60.3, 58.6, 57.5, 56.7, 51.7, 46.1, 44.0, 43.1, 40.1, 37.8, 34.8, 32.6, 28.5, 28.4. HRMS Calcd. For C₃₁H₃₃N₂O₅ [M + H]: 513.2389. Found: 513.2379.

Preparation of Trans-phenyl-4-oxo-2-phenyl-2-tetrahydro-2H-pyran-2-yl)piperidine-1-carboxylate (24). According the the general procedure, reaction of 160 mg (0.55 mmol) of dihydropyridone 5 with 142 mg (1.09 mmol) tetrahydropyran-2-carboxylic acid 23 in the presence of 190 mg (1.09 mmol) of HK₂PO₄ and 6.0 mg (8.2 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 120 mg (58%) of compound 24 as a separable 2:1 mixture of diastereomers: Major Isomer: colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.21 (m, 8.5H), 6.99 (br m, 1.5H), 5.80 (s, 1H), 4.44 (s, 1H), 4.00 (d, 1H, J = 10.8 Hz), 3.90 (d, 1H, J = 11.5 Hz), 3.61 (m, 1H), 3.44 (m, 1H), 2.95 (dd, 1H, J = 17.4 and 1.8 Hz), 2.67 (d, 1H, J = 17.4 Hz), 2.49 (br dd, 1H, J = 17.4 and 7.1 Hz), 1.89 (m, 1H), 1.66–1.49 (m, 4H), 1.34 (m, 1H); ¹³C-NMR (CDCl₃, 125 MHz) δ 206.1, 155.1, 151.0, 142.1, 129.3, 128.9, 127.3, 125.6, 125.3, 121.7, 79.4, 68.5, 57.0, 54.4, 45.1, 37.5, 28.3, 25.6, 23.4. HRMS Calcd. For C₂₃H₂₆NO₄ [M + H]: 379.1784. Found: 379.1784. Minor Isomer: colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 7.38 (t, 2H, J = 7.6 Hz), 7.26 (m, 5H), 7.17 (t, 1H, J = 7.3 Hz), 6.83 (br m, 2H), 5.74 (d, 1H, J = 5.7 Hz), 4.87 (m, 1H), 4.04 (d, 1H, J = 8.5 Hz), 3.65 (br m, 1H), 3.50–3.39 (m, 2H), 2.85–2.76 (m, 2H), 2.61 (dd, 1H, J = 17.7 and 1.5 Hz), 1.92 (m, 2H), 1.64–1.48 (m, 4H);); ¹³C-NMR (CDCl₃, 125 MHz) 206.3, 151.0, 145.2, 129.2, 128.9, 127.2, 125.5, 125.2, 121.6, 81.6, 69.1, 55.4, 45.8, 41.3, 28.8, 25.9, 23.4. HRMS Calcd. For C₂₃H₂₆NO₄ [M + H]: 380.1862. Found: 380.1849.

Preparation of Trans-phenyl 2-(2,3-dihydrobenzofuran-2-yl)-4-oxo-6-phenylpiperidine-1-carboxylate (26). According the the general procedure, reaction of 158 mg (0.54 mmol) of dihydropyridone 5 with 177 mg (1.08 mmol) of 2,3-dihydrobenzofuran-2-carboxylic acid 25 in the presence of 188 mg (1.08 mmol) of HK₂PO₄ and 9.1 mg (8.1 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 310 mg (65%) of compound 26 as a separable 3:1 mixture of diastereomers and rotamers in 82% combined yield. Major isomer: colorless solid; ¹H NMR (500 MHz, CDCl₃) δ 7.40 (m, 4H), 7.35 (m, 3H), 7.24 (t, J = 7.1 Hz, 1H), 7.16 (dd, J = 17.3, 7.7 Hz, 2H), 7.04 (br m, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.93 (d, J = 5.6 Hz, 1H), 5.49 (t, J = 8.8 Hz, 1H), 4.70 (d, J = 6.9 Hz, 1H), 3.75 (dd, J = 17.8, 6.4 Hz, 1H), 3.52 (dd, J = 16.3, 10.2 Hz, 1H), 3.09 (dd, J = 17.8, 1.9 Hz, 1H), 2.95 (dd, J = 16.3, 7.6 Hz, 1H), 2.55 (dd, J = 17.6, 7.4 Hz, 1H), 2.41 (d, J = 17.6 Hz, 1H). ¹³C-NMR (CDCl₃, 125 MHz) δ 205.3, 159.0, 150.9, 129.4, 129.3, 129.1, 129.0, 128.6, 128.3, 127.5, 127.4, 125.8, 125.6, 125.3, 125.2, 124.9, 121.6, 121.4, 121.3, 121.2, 109.5, 58.0, 55.4, 45.5, 44.7, 36.1, 33.1. Anal. Calcd. For C₂₆H₂₃NO₄: C, 75.53; H, 5.61; N, 3.39. Found: C, 75.39; H, 5.59; N, 3.33. Minor isomer: colorless solid contaminated with some of the major isomer; ¹H NMR (500 MHz, CDCl₃) δ 7.40 (m, 4H), 7.35 (m, 3H), 7.24 (t, J = 7.1 Hz, 1H), 7.16 (dd, J = 17.3, 7.7 Hz, 2H), 7.04 (br m, 2H), 6.94 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H), 5.70 (d, J = 6.5 Hz, 1H), 5.11 (t, J = 5.1 Hz, 1H), 4.95 (td, J = 8.9, 4.8 Hz, 1H), 3.51 (d, J = 10.2 Hz, 2H), 3.35 (d, J = 8.6 Hz, 2H), 2.79 (d, J = 18.0 Hz, 1H); ¹³C-NMR (CDCl₃, 125 MHz) δ 205.1, 204.4, 159.1, 158.4, 150.9, 150.8, 141.6, 129.7, 129.4, 129.3, 129.1, 129.0, 128.6, 127.5, 127.4, 126.5, 125.8, 125.7, 125.3, 125.2, 125.1, 125.0, 124.9, 121.7, 121.5, 121.3, 121.2, 109.5, 86.0, 84.0, 58.1, 55.4, 54.3, 36.1, 33.1. HRMS Calcd. For C₂₆H₂₄NO₄ [M + H]: 414.4810. Found: 414.4799.

Preparation of Trans-phenyl-4-oxo-2-phenyl-6-tetrahydrofuran-2-yl)piperidine-1-carboxylate (28). According the the general procedure, reaction of 150 mg (0.51 mmol) of dihydropyridone 5 with 119 mg (1.02 mmol) tetrahydrofuran2-carboxylic acid 27 in the presence of 178 mg (1.02 mmol) of HK₂PO₄ and 8.6 mg (7.6 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 131 mg (70%) of compound 28 as a separable 1:1 mixture of diastereomers: Major isomer: colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.26 (m, 7H), 7.21 (m, 1H), 7.00 (br m, 2H), 5.83 (d, 1H, J = 5.6 Hz), 4.65 (d, 1H, J = 6.5 Hz), 4.57 (t, 1H, J = 7.6 Hz), 3.73 (m, 2H), 3.67 (dd, 1H, J = 17.8 and 6.5 Hz), 3.00 (dd, 1H, J = 17.8 and 2.0 Hz), 2.53 (dd, 1H, J = 17.4 and 6.7 Hz), 2.45 (d, 1H, J = 16.8 Hz), 2.16 (m, 1H), 1.90 (m, 2H), 1.56 (m, 1H); ¹³C-NMR (CDCl₃, 125 MHz) δ 205.6, 151.0, 142.0, 129.3, 129.0, 127.3, 125.6, 125.3, 121.7, 80.9, 69.1, 56.6, 44.6, 36.8, 28.8, 25.8. HRMS Calcd. For C₂₂H₂₄NO₄ [M + H]: 366.1705. Found: 366.1699. Minor isomer: colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 7.40–7.20 (m, 7H), 7.17 (m, 1H), 6.86 (br m, 2H), 5.76 (d, 1H, J = 6.2 Hz), 4.81 (t, 1H, J = 6.2 Hz), 4.00–3.90 (m, 2H), 3.82 (q, 1H, J = 7.7 Hz), 3.48 (m, 1H), 2.87 (m, 2H), 2.60 (d, 1H, J = 17.9 Hz), 2.08 (m, 2H), 1.95 (m, 1H), 1.72 (m, 1H); ¹³C-NMR (CDCl₃, 125 MHz) δ 205.9, 151.1, 142.7, 129.3, 128.9, 127.3, 125.5, 125.2, 121.5, 82.2, 68.1, 55.3, 54.3, 45.6, 41.4, 29.4, 25.9. HRMS Calcd. For C₂₂H₂₄NO₄ [M + H]: 366.1705. Found: 366.1712.

Preparation of Tert-butyl 2-(1-tert-butoxycarbonyl)azetidin-2-yl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (31). According the the general procedure, reaction of 159 mg (0.65 mmol) of 4-oxoquinolinone 29 with 261 mg (1.23 mmol) of N-Boc-azetidine-2-carboxylic acid 13 in the presence of 182 mg (1.23 mmol) of HK₂PO₄ and 10.9 mg (9.72 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 100 mg (38%) of compound 31 as a separable mixture of diatereomers. Isomer A: ¹H NMR (500 MHz, CDCl₃) δ 7.98 (dd, J = 7.8, 1.4 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54–7.45 (m, 1H), 7.17 (t, J = 7.5 Hz, 1H), 5.12–5.01 (m, 1H), 4.26–4.14 (m, 1H), 3.96–3.78 (m, 2H), 3.19 (d, J = 18.3 Hz, 1H), 2.98 (dd, J = 18.3, 6.2 Hz, 1H), 2.26 (p, J = 10.0, 9.6 Hz, 1H), 2.08 (ddt, J = 11.3, 8.8, 5.7 Hz, 1H), 1.58 (s, 9H), 1.42 (s, 9H). ¹³C-NMR (CDCl₃, 125 MHz) δ 192.6, 157.1, 153.1, 141.6, 133.8, 126.8, 125.7, 124.8, 124.0, 61.7, 57.7, 46.9, 20.3. HRMS Calcd. For C₂₂H₃₁N₂O₅: 403.4990. Found: 403.4986. Isomer B: ¹H NMR (500 MHz, CDCl₃) δ 7.91 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 5.09 (t, J = 6.3 Hz, 1H), 4.39 (dt, J = 8.6, 5.6 Hz, 1H), 3.75–3.47 (m, 2H), 3.12 (dd, J = 18.3, 7.4 Hz, 1H), 2.89 (d, J = 18.3 Hz, 1H), 2.28 (s, 1H), 2.01 (d, J = 22.3 Hz, 1H), 1.57 (s, 9H), 1.36 (s, 9H). ¹³C-NMR (CDCl₃, 125 MHz) δ 192.7, 156.0, 153.4, 142.7, 133.7, 126.3, 125.0, 123.6, 82.1, 56.1, 46.8, 40.0, 28.4, 28.2, 19.4. HRMS Calcd. For C₂₂H₃₁N₂O₅ [M + H]: 403.4990. Found: 403.4999.

Preparation of Tert-butyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-oxo-3,4-dihydroquinoline-1(2H) Carboxylate (32). According the the general procedure, reaction of 128 mg (0.52 mmol) of 4-oxoquinolinone 29 with 225 mg (1.04 mmol) of N-Boc-L-proline 11 in the presence of 182 mg (1.04 mmol) of HK₂PO₄ and 8.8 mg (7.83 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 120 mg (55%) of compound 32 as a colorless oil and an inseparable 1:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 8.05–7.71 (br m, 1H), 7.78, 7.60 and 7.5 (m, 2H), 7.20–7.10 (m, 1H), 4.87 and 4.60 (m, 1H), 4.15–3.93 (m, 1.90H), 3.04 (dd, 0.26H, J = 17.8 and 6.9 Hz), 2.94–2.89 (m, 2H), 2.05–1.85 (br m, 3.7H), 1.68 (m, 1H), 1.56 and 1.55 (s, 9H), 1.35 (br m, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 192.8, 192.7, 155.1, 154.6, 153.4, 153.2, 143.7, 141.3, 133.8, 133.5, 132.8, 127.0, 126.3, 126.2, 125.2, 125.1, 124.2, 123.2, 82.4, 81.0, 59.1, 57.8, 57.2, 56.6, 53.9, 46.8, 46.2, 45.9, 40.9, 40.8, 40.2, 39.7, 28.4, 28.3, 28.2, 28.0, 23.8, 23.5, 22.7, 22.3. HRMS Calcd. For C₂₃H₃₃N₂O₅ [M + H]: 417.5260. Found: 417.5251.

Preparation of Tert-butyl (2-(1-(tert-butoxycarbonyl)piperidin-2-yl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (33). According the the general procedure, reaction of 164 mg (0.67 mmol) of 4-oxoquinolinone 29 with 310 mg (1.37 mmol) of N-Boc-pipecolic acid 14 in the presence of 233 mg (1.37 mmol) of HK₂PO₄ and 11 mg (10.0 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 160 mg (55%) of compound 33 as a colorless oil and as inseparable 4:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 8.03 and 8.97 (d, 1H, J = 7.8 Hz), 7.71–7.45 (m, 2H), 7.20 (m, 1H), 5.36 and 5.24 (m, 1H), 4.36 and 4.21 (m, 1H), 4.13 (m, 0.8H), 4.01–3.80 (m, 0.4H), 3.14–3.01 (m, 0.7H), 2.91 (dd, 0.8 H, J =18.3 and 6.0 Hz), 2.78–2.57 (m, 1.8H), 1.84–1.64 (m, 5H), 1.51 (s, 10.8H), 1.44–1.35 (m, 2H), 1.33 (s, 6H); ¹³C-NMR (CDCl₃, 125 MHz) δ 192.9, 192.5, 192.1, 154.4, 152.9, 142.1, 141.1, 140.8, 134.3, 133.8, 133.5, 127.2, 126.9, 126.5, 126.2, 125.9, 125.8, 125.5, 125.2, 124.5, 124.3, 123.8, 82.4, 80.6, 51.5, 50.7, 50.3, 50.1, 48.8, 48.7, 40.7, 40.4, 39.9, 39.4, 38.7, 28.5, 28.3, 27.9, 26.0, 25.2, 25.1, 24.7, 19.2. HRMS Calcd. For C₂₄H₃₅N₂O₅ [M + H]: 431.5530. Found: 431.5528.

Preparation of Tert-butyl-3-(1-(tert-butoxycarbonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-2-yl)morpholine-4-carboxylate (34). According the (the general procedure, reaction of 106 mg (0.43 mmol) of 4-oxoquinolinone 29 with 200 mg (0.87 mmol) of 4-Boc-3-morpholinecarboxylic acid 16 in the presence of 151 mg (0.87 mmol) of HK₂PO₄ and 7.3 mg (6.5 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 122 mg (65%) of compound 34 as a colorless foam and as inseparable 4:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 8.01 and 8.00 (m, 1H), 7.79–7.60 (m, 1H), 7.54 (m, 1H), 7.20 (m, 1H), 5.57 and 5.50 (m, 1H), 4.10 and 4.02 (m, 1.2H), 3.94–3.74 (m, 3H), 3.57–3.34 (m, 2.5H), 3.15 (dd, 0.5H, J = 17.9 and 5.5 Hz), 3.07–2.93 (m, 1.3H), 2.82 (t, 0.3H, J = 17.7 and 5.5 Hz), 2.69 and 2.55 (d, 0.51H, J = 18.3 Hz), 1.59 (m, 9.5H), 1.46 and 1.41 (s, 4H), 1.36 (s, 5H), 1.10 (s, 1.8 Hz); ¹³C-NMR (CDCl₃, 125 MHz) δ 192.7, 192.1, 191.6, 154.1, 154.0, 152.9, 152.8, 142.2, 141.2, 140.9, 134.5, 134.0, 133.6, 127.3, 127.1, 126.6, 126.2, 125.7, 125.5, 125.3, 125.1, 124.5, 124.2, 124.0, 123.9, 82.9, 82.7, 82.4, 81.1, 67.4, 67.0, 66.9, 66.7, 66.4, 66.0, 65.8, 51.5, 50.9, 50.2, 49.6, 49.3, 40.6, 40.2, 38.9, 38.7, 28.3, 28.1, 27.9. HRMS Calcd. For C₂₃H₃₃N₂O₅ [M + H]: 433.5250. Found: 433.5243.

Preparation of Tert-butyl 2-(4-oxochroman-2-yl)pyrrolidine-1-carboxylate (35). According the the general procedure, reaction of 157 mg (1.07 mmol) of 4H-chromen-4-one 30 with 462 mg (2.15 mmol) of N-Boc-L-proline 11 in the presence of 374 mg (2.15 mmol) of HK₂PO₄ and 18 mg (0.016 mmol) of(Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 310 mg (65%) of compound 35 as a colorless foam and as inseparable 1:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.90 (m, 1H), 7.49 (m, 1H), 7.00 (br m, 2H), 4.85–4.54 (br m, 1H), 4.27 (br m, 0.5H), 4.05 (br m, 0.5H), 3.69–3.35 (br m, 2H), 2.78 (m, 1H), 2.67 (m, 1H), 2.25 (m, 0.5H), 2.14–1.88 (br m, 3.5H), 1.48 (s, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 192.5, 192.0, 161.5, 156.2, 155.0, 135.8, 126.9, 126.8, 121.2, 120.9, 118.0, 117.8, 80.1, 79.5, 78.9, 78.4, 77.9, 59.8, 58.8, 47.3, 47.1, 46.7, 42.0, 39.9, 39.4, 28.5, 27.7, 26.6, 25.7, 24.5, 24.2, 23.6, 23.3. HRMS Calcd. For C₁₈H₂₄NO₄ [M + H]: 317.1627. Found: 317.1624.

Preparation of Tert-butyl-2-(4-oxochroman-2-yl)indoline-1-carboxylate (36). According the the general procedure, reaction of 157 mg (1.07 mmol) of 4H-chromen-4-one 30 with 424 mg (2.15 mmol) of N-Boc-indoline-2-carboxylic acid 21 in the presence of 374 mg (2.15 mmol) of HK₂PO₄ and 18 mg (0.016 mmol) of Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 240 mg (61%) of compound 36 as a colorless oil as an inseparable 1:1 mixture of diastereomers and rotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.87 (m, 1H), 7.48 (m, 1H), 7.20 (m, 2H), 7.05–6.89 (m, 3H), 4.95 (br m, 1H), 4.74 and 4.70 (br m, 1H), 3.42 (m, 1H), 3.34–3.23 (m, 1H), 2.90 (dd, J = 15.0, 10.0 Hz, 0.5 H), 2.72 (dd, J = 15.0, 5.0 Hz, 0.5H), 2.62 (dd, J = 15.0 and 14.0 Hz, 0.5H), 2.49 (dd, J = 15.0, 5.0 Hz, 0.5H), 1.60 (s, 9H). ¹³C-NMR (CDCl₃, 125 MHz) δ 191.9, 191.5, 161.4, 161.3, 136.0, 135.8, 127.7, 127.4, 127.0, 126.9, 124.7, 124.5, 123.1, 123.0, 121.5, 121.1, 120.9, 118.1, 117.9, 115.9, 115.7, 78.1, 77.1, 61.5, 60.3, 39.9, 37.1, 28.4. HRMS Calcd. For C₂₂H₂₄NO₄ [M + H]: 366.4370. Found: 366.4366.

Preparation of 2-(Tetrahydrofuran-2-yl)chroman-4-one (37). According the the general procedure, reaction of 133 mg (0.91 mmol) of 4H-chromen-4-one 30 with 211 mg (1.82 mmol) of tetrahydrofuran2-carboxylic acid 27 in the presence of 317 mg (1.82 mmol) of HK₂PO₄ and 15 mg (0.14 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 135 mg (68%) of compound 37 as a separable 1:1 mixture of diastereomers and as colorless oils: Isomer 1: ¹H NMR (500 MHz, CDCl₃) δ 7.90 (dd, J = 7.8, 1.3 Hz, 1H), 7.54–7.44 (m, 1H), 7.07–6.97 (m, 2H), 4.41 (dt, J = 11.9, 4.5 Hz, 1H), 4.20 (q, J = 6.7 Hz, 1H), 3.95 (q, J = 6.7 Hz, 1H), 3.86 (q, J = 6.8 Hz, 1H), 2.90–2.72 (m, 2H), 2.21–2.07 (m, 1H), 1.95 (M, 3H). ¹³C-NMR (CDCl₃, 125 MHz) δ 192.2, 161.4, 136.0, 126.9, 121.4, 121.1, 118.0, 79.7, 79.4, 69.0, 39.0, 27.6, 25.7. Isomer 2: ¹H NMR (500 MHz, CDCl₃) δ 7.90 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.14–6.97 (m, 2H), 4.43 (ddd, J = 13.1, 5.0, 2.9 Hz, 1H), 4.14 (q, J = 7.0 Hz, 1H), 4.03–3.72 (m, 2H), 2.93 (dd, J = 16.7, 13.2 Hz, 1H), 2.68 (dd, J = 16.7, 2.8 Hz, 1H), 2.15–1.83 (m, 4H). ¹³C-NMR (CDCl₃, 125 MHz) δ 192.1, 161.3, 136.1, 126.8, 121.3, 120.9, 118.1, 79.8, 79.7, 68.9, 39.8, 27.5, 25.9.

Preparation of tert-Butyl 2-(4-oxochroman-2-yl)piperidine-1-carboxylate (38). According the the general procedure, reaction of 239 mg (1.64 mmol) of 4H-chromen-4-one 30 with 750 mg (3.27 mmol) of N-Boc-pipecolic acid 15 in the presence of 570 mg (3.27 mmol) of HK₂PO₄ and 18.3 mg (0.016 mmol) of (Ir[dF(CF₃)ppy]2(dtbpy))PF₆ provided 500 mg (92%) of compound 38 as a separable 1:1 mixture of diastereomers and rotamers: Isomer #1: colorless solid; ¹H NMR (500 MHz, CDCl₃) δ 7.92 (dd, 1H, J = 7.18 and 1.6 Hz), 7.50 (m, 1H), 7.05 (t, 1H, J = 7.5 Hz), 7.01 (d, 1H, J = 8.3 Hz), 4.74 (m, 1H), 4.50 (br m, 1H), 4.14 (br m, 1H), 2.75 (m, 3H), 2.23 (m, 1H), 1.75–1.60 (m, 5H), 1.49 (s, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 191.9, 161.1, 154.8, 135.9, 127.0, 121.5, 121.2, 117.9, 80.1, 74.8, 52.7, 39.9, 28.4, 25.1, 24.2, 19.2. Anal. Cald. For C₁₉H₂₅NO₄: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.96; H, 7.55; N, 4.19. Isomer #2: colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 7.90 (dd, 1H, J = 7.9 and 1.6 Hz), 7.49 (m, 1H), 7.04 (m, 1H), 6.97 (d, 1H, J =8.3 Hz), 4.73 (q, 1H, J = 7.7 Hz), 4.50 (br m, 1H), 4.15 (br m, 1H), 2.96 (br m, 1H), 2.77 (m, 2H), 1.78 (m, 2H), 1.70 (m, 3H), 1.53 (m, 1H), 1.49 (s, 9H); ¹³C-NMR (CDCl₃, 125 MHz) δ 192.0, 161.3, 155.5, 136.0, 126.8, 121.4, 120.9, 118.1, 79.6, 53.0, 40.7, 39.9, 28.4, 25.8, 25.0, 19.8. Anal.Calcd. for C₁₉H₂₆NO₄ [M + H]: 332.1862. Found: 332.1870.

4. Conclusions

In conclusion, we have demonstrated that the photoredox-catalyzed decarboxylative formation of carbon-centered radicals from cyclic amino acids followed by conjugate addition to both cyclic vinylogous amides and esters provides access to novel heterocyclic structures. This versatile method is both mild and efficient giving rise to structural complexity previously inaccessible through current synthetic methodologies. Further manipulation of the products toward more complex synthetic targets is possible and will be disclosed in due course.