Polysubstituted Pyridines from 1,4-Oxazinone Precursors

Abstract

This study describes a general method for the preparation of 1,4-oxazin-2-one intermediates from acetylene dicarboxylate and β-amino alcohol precursors. Oxazinones prepared in this manner were employed in a tandem cycloaddition/cycloreversion reaction sequence with a model alkyne (phenyl acetylene) to give substituted pyridine products. Fundamental reactivity and selectivity studies are complemented by the synthesis of the polycyclic ergot alkaloid natural product xylanigripone A.

Introduction

The pyridine ring is a privileged heterocyclic scaffold in medicinal chemistry and is frequently present in therapeutic bioactive molecules, agrochemicals, and natural products.^1,2 Recent technologies focused on C–H activation and functionalization of pyridines and related derivatives (such as pyridinium ions) through both ionic and radical (e.g., Minisci-like) processes have enabled several distinct strategies for derivatization of the pyridine nucleus.³⁻¹³ The preparation of highly substituted pyridine motifs either by classic condensation strategies, modern de novo methods of construction, or by C–H activation of intact pyridines remains a challenge. Highly substituted pyridines, such as 2,6-disubstituted variants, can fail in the pyridinium formation or other N-activation step. Merged cycloaddition/cycloreversion processes have proven a reliable method for the preparation of highly substituted aromatic heterocycles and carbocycles.¹⁴⁻¹⁸

1,4-Oxazinone precursors resembling 1 are the most reactive substrates that can undergo cycloaddition/cycloreversion sequences leading to pyridines (Figure 1). This pericyclic reaction subgroup includes 1,4-oxazinones, 1,2,4-, and 1,2,3-triazines, as well as diazines and other heterocyclic precursors. Computational predictions suggest that 1 has cycloaddition activation energies approximately 4 kcal/mol lower than the complementary 1,2,4-triazine, a more commonly used reactive precursor for the synthesis of pyridines by merged cycloaddition/cycloreversion sequences.¹⁹ The increased reactivity of oxazinones allow reaction under both normal- and inverse-electron-demand conditions and 1 is competent with a wide array of 2π reaction components, including unactivated alkynes.²⁰⁻²² Cycloaddition with alkynes gives the resulting intermediate adduct represented by 2 (or its regioisomeric complement). The intermediate [2.2.2]bicycloalkene is generally not stable even at ambient temperatures and undergoes extrusion of CO₂ to afford pyridine products such as 3.²³

Figure 1.

Diels–Alder/retro Diels–Alder sequence with 1,4-oxazinone.

Our lab is interested in advancing new methods for the construction of oxazinone precursors and exploring their reactivity in the preparation of complex pyridines. This manuscript aligns with this focus and describes a general method for the synthesis of oxazinones from β-amino alcohols and acetylene dicarboxylate. The reactivity of the oxazinones thus produced, as well as the isomeric selectivity in the pyridines obtained through a merged [4 + 2]/retro[4 + 2], is also explored in this report.

The preparation of oxazinone precursors has largely followed the original conditions reported by Hoornaert and co-workers where cyanohydrin derivatives are consumed with excess oxalyl chloride at elevated temperatures (>90 °C) leading to the 3,5-dichloro substituted oxazinones represented by 4 (Figure 2, eq 1).^24,25 More recently, other conditions have been reported for the preparation of oxazinones bearing other substitution patterns, in particular, those bearing alkyl and aryl groups at positions 3 and 5.²⁶ We reported a route to oxazinone 8a from acetylene dicarboxylate (DMAD, 5) and aminopropane-1,3-diol 6 (Figure 2, eq 2).²⁷ For this particular oxazinone (8a), heteroconjugate addition, lactonization, and acylation gives an intermediate dihydrooxazinone 7 (in 51% or 80% yield following recrystallization or chromatography). Elimination of the acetate in 7 with NEt₃ in toluene at 110 °C and concomitant isomerization gave the 5-methyloxazinone 8a, which exists in the exocyclic vinylogous urethane tautomer. Oxazinone 8a has proven competent in the cycloaddition/cycloreversion sequence with several alkynes.^27,28

Figure 2.

Original and recent method preparing oxazinone intermediates.

Results and Discussion

Although the sequence from DMAD (5) to 5-methyloxazinone 8a was effective, the nature of the synthesis was specific. We wish to report a complementary and more general sequence to prepare Diels–Alder reactive oxazinones from a variety of β-amino alcohols and acetylene dicarboxylate precursors. Using the chemistry highlighted in Table 1, eight oxazinone intermediates were prepared which feature different groups at position 5 (8a–8d, entries 1–4,), position 6 (8e and 8f, entries 5, 6) and the two 5,6-disubsituted variants 8g and 8h (entries 7, 8). The route toward oxazinones 8a–8e begins with heteroconjugate addition of the β-amino alcohol substrate. The resulting addition product (not shown) undergoes lactonization to the dihydrooxazinone represented by structure 9. In accord with gearing effects analogous to those described by Thorpe and Ingold,²⁹ amino alcohol substrates with substitution proximal to the amino function (R¹ = C) underwent spontaneous lactonization to 9 at ambient temperatures; substrates lacking substitution or bearing a smaller group at position 5 (entries 5, 6, 8) required heating in methanol (66 °C) to promote lactone formation.

Table 1. Preparation of Oxazinone Precursors and Cycloaddition/cycloreversion to Afford Pyridine Products.

^aKey: Oxazinone 8a prepared through a modified sequence. See experimental information for details.

^bAcylation was performed on the intermediate dihydrooxazinone 9 (where R¹ = CH₂OH to CH₂OAc)

^cDBU was used for dehydrobromination to give 8c and 8h.

Although several net oxidations were considered, we found that a bromination/dehydrobromination sequence was reliable for the conversion of dihydrooxazinone precursors (9) into the Diels–Alder-reactive substrates represented by 8. This was accomplished by exposing 9 to NBS in MeCN, followed by elimination using NEt₃. All oxazinones were prepared in this manner excluding substrates 8c and 8h, where a stronger organic base (DBU) was employed for the dehydrobromination step.

The merged cycloaddition/cycloreversion of oxazinones 8a–8h was explored using a model alkyne, phenylacetylene (Table 1). Efficient reaction was observed in all cases and, overall, 5-substituted oxazinones provided the resulting pyridines 10a–10d in excellent isomeric purity; little to none of the 4-phenyl pyridine isomer 11 was observed in these cases. Reaction with either the 6-substituted oxazinones (8e and 8f) or oxazinones bearing 5,6-disubstitution (8g and 8h) showed lower regioselectivity in the cycloaddition event and the derived pyridine products were afforded as isomeric mixtures ranging from 6:1 to 1:1.

Although the 6-methyloxazinone 8e was unselective with phenyl acetylene and gave the resulting pyridines 10e and 11e in a 1:1 ratio, the merged cycloaddition/cycloreversion sequence with 2-ethynyl benzaldehyde (12) gave a single isomer of the fused tricyclic pyridine 13 (Scheme 1). This reaction was very clean, and no other products were observed in the unpurified reaction mixture; only a small amount of unreacted starting material was present. Pyridine 13 can arise from a domino reaction sequence comprised of cycloaddition, extrusion of CO₂ (cycloreversion), and aldol condensation. Either intermediate 14a or 14b could be operational in the regioselective synthesis of 13. We were not certain whether the pericyclic processes precede an intramolecular aldol condensation, or the alternate scenario, where the aldol condensation ensues prior to an intramolecular cycloaddition. The exceptional improvement in regioselection as compared to phenylacetylene possibly supports the later mechanistic sequence and interception of the intermediate 14b.

Scheme 1. Merged Cycloaddition, Cycloreversion, and Aldol Condensation with 2-ethynylbenzaldehyde.

In order to gain a deeper understanding of the mechanistic sequence of events leading from oxazinone 8e and 1-ethynylbenzaldehyde (12) to the tricycylic product 13, we performed an analogous sequence using 2-nitrophenylacetylene (15) (Scheme 2). Nitrophenylacetylene possesses a similar electronic and steric profile to 12; however, lacking the 2-carboxaldehyde function, it cannot participate in the aldol condensation. In the event, reaction of oxazinone 8e and nitrophenylacetylene 15 afforded both pyridine isomeric products 16a and 16b in a 3:2 ratio as judged by ¹H NMR analysis of the unpurified reaction mixture. The structure of the major isomer 16a was confirmed by NOE. This experiment demonstrates that incorporation of an electron withdrawing group on phenyl acetylene (such as the nitro group in 15) has only a modest impact on the cycloaddition regioselectivity. This unexceptional selectivity increase (from 1:1 with phenyl acetylene to 3:2 with nitrophenylacetylene) suggests that the reaction between 8e and 1-ethynylbenzaldehyde (12) likely proceeds by aldol condensation prior to pericyclic operations.

Scheme 2. Cycloaddition and Cycloreversion with 2-Nitrophenylacetylene.

We recognized that an analogous domino reaction sequence might enable access to the tetracyclic pyridine scaffold present in xylanigripone A (20), an unusual ergot alkaloid isolated from the rare Xylaria nigripes fungi present in abandoned termite nests (Scheme 3).³⁰ Historically, Xylaria fungal sources have been used to treat diseases of the digestive and central nervous systems.³¹⁻³³ The xylanigripones and related derivatives could serve as important scaffolds for development; however, these compounds are obtained in small quantities from the fungi. Since isolation of the xylanigripones in 2017, two syntheses of xylanigripone A have been disclosed.^34,35

Scheme 3. Synthesis of Xylanigripone A.

Our synthetic strategy toward xylanigripone A (20) initiated from 6-methyloxazinone 8e. Union of this starting material with the derived alkynyl isatin 17 led, following aldol condensation and [4 + 2]/retro[4 + 2], to the fused pyridine product 18 as a single isomer in 78% yield. Concomitant cleavage of the methyl ester and silyl function in 18 was achieved with LiOH in MeOH/THF at 50 °C to give penultimate intermediate 19. Intermediate 19 was challenging to manipulate due to the presence of both pyridine and carboxylic acid moieties. Compound 19 was precipitated directly from the hydrolysis reaction and used without purification in the final operation, a copper-catalyzed decarboxylation, to deliver the natural product xylanigripone A (20) in 31% yield from 18 (2 steps).³⁶ Overall, the synthetic route to 20 was accomplished in 6 total steps from common reagents (5 steps by the longest linear route).

In conclusion, this report advances a general strategy for the construction of substituted oxazinone precursors from readily available starting materials, β-amino alcohols and acetylene dicarboxylate. Oxazinones prepared by this method were explored in merged cycloaddition/cycloreversion reaction sequences with alkyne reaction components. This chemistry adds to our current knowledge of the reactivity and selectivity of oxazinone intermediates and increases the synthetic utility of these precursors for complex pyridine synthesis. The “one pot” selective construction of the fused polycyclic pyridine products by merging an aldol condensation with the pericyclic processes enabled the efficient construction of the ergot alkaloid skeleton present in xylanigripone A.

Experimental Section

General Experimental Considerations

All reactions were carried out under an atmosphere of nitrogen in flame-dried or oven-dried glassware with magnetic stirring or in vials sealed with a Teflon cap. Reagents were used as received. Flash column chromatography was performed using P60 silica gel (230–400 mesh). Analytical thin layer chromatography (TLC) was performed on SiliCycle 60 Å glass plates. Visualization was accomplished with UV light, ceric ammonium molybdate or potassium permanganate, followed by heating. Infrared spectra were recorded using a Digilab FTS 7000 FTIR spectrophotometer. ¹H NMR spectra were recorded on a 400 MHz spectrometer and are reported in ppm using solvent as an internal standard (CHCl₃ at 7.26 ppm) or tetramethylsilane (0.00 ppm). Proton-decoupled ¹³C NMR spectra (¹³C{¹H} NMR) were recorded with a 100 MHz spectrometer and are reported in ppm using solvent as an internal standard (CHCl₃ at 77.0 ppm, DMSO at 39.5 ppm, pyridine at 150.29 ppm). All compounds were judged to be homogeneous (>95% purity) by ¹H and ¹³C NMR spectroscopy unless otherwise noted. Mass spectra data analysis was obtained through positive electrospray ionization (w/NaCl) on a Bruker 12 T APEX–Qe FTICR-MS with an Apollo II ion source using an ICR (ion cyclotron resonance) ion trap mass analyzer.

General Procedure A

Preparation of 1,4-Oxazinone 8

A dry flask was charged with a 1,2-amino alcohol (1 equiv) and dissolved in MeOH (0.2 M). The flask was flushed with N₂ (10 min) and DMAD (1 equiv) was added dropwise. The reaction was allowed to stir at rt until the addition and lactone formation was complete as judged by TLC (1 h). If lactone formation was not complete after 1 h, the reaction mixture was fitted with a condenser and heated to reflux using an aluminum heating block. Following lactone formation, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeCN (0.2 M) and flushed with N₂ (10 min). The reaction was cooled to 0 °C and NBS (1 equiv) was added. After stirring for 5 min at 0 °C, NEt₃ (2 equiv) was introduced, and the reaction was stirred at rt until dehydrobromination was complete (0.5–16 h) as judged by TLC. The reaction mixture was transferred to separatory funnel and partitioned between 0.1 M HCl and Et₂O. The organic portion was removed, and the aqueous portion was extracted with additional Et₂O. The combined organic portions were washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (gradient elution: EtOAc/hexane) to afford the desired 1,4-oxazinone products 8.

The experimental reaction conditions and data for oxazinone 8a and pyridine 10a are reported elsewhere.²⁷ Conditions and data for all new compounds are disclosed below.

Methyl(Z)-2-(5-(acetoxymethyl)-2-oxo-2H-1,4-oxazin-3(4H)-ylidene)acetate (8b)

This compound was prepared using a modified version of general procedure A: A dry flask was charged with dihydrooxazinone precursor 7²⁷ (1.0 g, 4.11 mmol) and dissolved in MeCN (21 mL, 0.2M). The flask was flushed with N₂ for 10 min and cooled to 0 °C. NBS (0.73 g, 4.11 mmol) was added in one portion. The reaction mixture was then stirred for 15 min at 0 °C, until bromination was complete as judged by TLC. NEt₃ (1.15 mL, 8.22 mmol) was then added dropwise, and the reaction was stirred for 15 min until elimination was complete as judged by TLC. The resulting mixture was transferred to a separatory funnel and partitioned between 0.5 M HCl (10 mL) and Et₂O (10 mL). The organic layer was removed, and the aqueous layer was extracted with additional Et₂O (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (gradient elution: 10 to 80% EtOAc in hexane) to afford oxazinone 8b as a light-yellow amorphous solid (320 mg, 33% yield). TLC (20% EtOAc), R_f: 0.25 (CAM); IR (film) 3123, 1744, 1630, 1429, 1262, 764 cm^–1; ¹H NMR (400 MHz, CDCl₃) 10.29 (s, 1H), 6.49 (d, J = 2.4 Hz, 1H), 5.85 (d, J = 0.8 Hz, 1H), 4.68 (s, 2H), 3.77 (s, 3H), 2.15 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.1, 169.7, 156.1, 138.3, 125.0, 118.3, 90.0, 59.3, 51.3, 20.5; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₀H₁₁NO₆Na⁺ 264.0478; Found 264.0477.

Methyl (Z)-2-(5-Isopropyl-2-oxo-2H-1,4-oxazin-3(4H)-ylidene)acetate (8c)

Oxazinone 8c was synthesized following a modified general procedure A, using DBU in the place of NEt₃, to afford an amorphous yellow solid (980 mg, 61% yield). TLC (10% EtOAc), R_f: 0.60 (CAM); IR (film) 1745, 1653, 1250, 1159, 1031, 626 cm^–1; ¹H NMR (400 MHz, CDCl₃) 10.22 (s, 1H), 6.27 (d, J = 2.0 Hz, 1H), 5.80 (s, 1H), 3.76 (s, 3H), 2.52 (sept, J = 7.2 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.7, 157.0, 139.6, 127.4, 121.1, 88.2, 51.3, 27.9, 20.3; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₀H₁₃NO₄Na⁺ 234.0737; Found 234.0738.

Methyl (Z)-2-(2-Oxo-5-phenyl-2H-1,4-oxazin-3(4H)-ylidene)acetate (8d)

Following general procedure A, oxazinone 8d was prepared as a yellow powder (54 mg, 43% yield). Mp 136–142 °C; TLC (20% EtOAc), R_f: 0.5 (CAM); IR (film) 3941, 3252, 3130 3005, 2955, 2845, 1794, 1661, 1614, 1435, 1282, 1261, 1198, 1180, 1147, 1030, 1015, 760 cm^–1; ¹H NMR (400 MHz, CDCl₃) 10.65 (s, 1H), 7.47–7.34 (m, 5H), 6.73 (d, J = 2.8 Hz, 1H), 5.91 (s, 1H), 3.78 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.6, 156.5, 139.0, 130.0, 129.6, 129.4, 124.7, 123.0, 122.5, 89.4, 51.4; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₃H₁₁NO₄Na⁺ 268.0580; Found 268.0581.

Methyl (Z)-2-(6-Methyl-2-oxo-2H-1,4-oxazin-3(4H)-ylidene)acetate (8e)

Following general procedure A, oxazinone 8e was prepared as an amorphous yellow solid (790 mg, 51% yield). TLC (60% EtOAc in hexane), R_f: 0.95 (CAM); IR (film) 1744, 1651, 1601, 1435, 1269, 1138, 1084, 764 cm^–1; ¹H NMR (400 MHz, CDCl₃) 10.03 (s, 1H), 5.99 (d, J = 2.8 Hz, 1H), 5.76 (s, 1H), 3.73 (s, 3H), 2.01 (d, J = 1.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.6, 157.4, 138.6, 134.8, 105.0, 87.5, 51.2, 16.1; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₈H₉NO₄Na⁺ 206.0424; Found 206.0424.

(Z)-2-Ethylidene-5-Phenyl-1,4-dihydropyridin-3(2H)-one--carbon dioxide (8f)

Oxazinone 8f was synthesized following a modified general procedure A. After 24 h of heating in MeOH to promote lactonization, a portion of unlactonized material remained and was removed through chromatographic separation (gradient elution: 7–100% EtOAc in hexanes) before proceeding with the bromination/elimination sequence. Oxazinone 8f was obtained as a yellow powder (390 mg, 31% yield). Mp: 160–166 °C; TLC (20% EtOAc in hexane), R_f: 0.40 (CAM); IR (film) 1761, 1748, 1593, 1435, 1146, 758 cm^–1; ¹H NMR (400 MHz, CDCl₃): 10.39 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.41–7.29 (m, 4H), 6.74 (d, J = 5.6 Hz, 1H), 5.89 (s, 1H), 3.77 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.4, 156.7, 138.1, 136.4, 130.4, 129.2, 128.8, 128.3, 122.7, 105.1, 89.2, 51.4; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₃H₁₁NO₄Na⁺ 268.0580; Found 268.0580.

Methyl (Z)-2-(2-Oxo-5,6-diphenyl-2H-1,4-oxazin-3(4H)-ylidene)acetate (8g)

Following general procedure A, oxazinone 8g was prepared as an amorphous yellow solid (490 mg, 49% yield). TLC (10% EtOAc), R_f: 0.60 (CAM); IR (film) 1755, 1622, 1312, 1275, 1252, 694 cm^–1; ¹H NMR (400 MHz, CDCl₃) 10.44 (s, 1H), 7.39 (s, 5H), 7.21 (s, 5H), 5.90 (s, 1H), 3.75 (s, 3H) ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 1.1, 186.5, 170.6, 156.8, 138.4, 133.3, 132.2, 131.2, 129.6, 129.4, 128.8, 128.3, 128.1, 127.9, 119.6, 88.5, 51.4; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₉H₁₅NO₄Na⁺ 344.0893; Found 344.0895.

Methyl (Z)-2-(2-Oxo-5,6,7,8-tetrahydro-2H-benzo[b][1,4]oxazin-3(4H)-ylidene)acetate (8h)

Oxazinone 8h was synthesized following a modified general procedure A, using DBU in the place of NEt₃, to afford an amorphous yellow solid (57 mg, 75% yield). TLC (20% EtOAc), R_f: 0.25 (CAM); IR (film) 1748, 1620, 1341, 1136, 768 cm^–1; ¹H NMR (400 MHz, CDCl₃) 9.90 (s, 1H), 5.74 (s, 1H), 3.74 (s, 3H), 2.32 (m, 4H), 1.75 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.7, 157.6, 139.7, 132.3, 114.5, 87.9, 51.1, 24.8, 24.4, 21.8, 21.6; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₁H₁₃NO₄Na⁺ 246.0736; Found 246.0737.

General Procedure B

Synthesis of Pyridine Isomers 10 and/or 11 through [4 + 2]/retro[4 + 2].

A dry flask was charged with oxazinone 8 and dissolved in a 1:1 mixture of PhMe and phenylacetylene (0.5M). The vial was flushed with N₂ (5 min), sealed with a Teflon cap, and heated to 110 °C overnight using an aluminum heating block. After cooling rt and concentration in vacuo, the resulting unpurified reaction mixture was analyzed by ¹H NMR to determine the isomeric ratio of pyridines 10 and 11. The mixture was purified by flash column chromatography on silica gel (gradient elution: EtOAc/hexane).

Methyl 2-(6-(Acetoxymethyl)-3-phenylpyridin-2-yl)acetate (10b)

Following general procedure B, pyridine 10b was synthesized as a light-yellow oil (61 mg, 66% yield). TLC (30% EtOAc in hexane), R_f: 0.68 (CAM); IR film 3059, 2951, 1736, 1591, 1435, 1007, 704 cm^–1; ¹H NMR (400 MHz, CDCl₃) 7.60 (d, J = 7.6 Hz, 1H), 7.44–7.30 (m, 6H), 5.26 (s, 2H), 3.84 (s, 2H), 3.64 (s, 3H), 2.18 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) 171.2, 170.6, 154.4, 151.8, 138.7, 138.4, 136.9, 128.9, 128.5, 127.9, 120.2, 66.7, 51.9, 41.6, 20.9; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₇H₁₇NO₄H⁺ 300.1230; Found 300.1229.

Methyl 2-(6-Isopropyl-3-phenylpyridin-2-yl)acetate (10c)

Following general procedure B, pyridine 10c was synthesized as a light-yellow oil (48 mg, 93% yield). TLC (10% EtOAc in hexane), R_f: 0.60 (CAM); IR film 1740, 1591, 1436, 1158, 1007, 726 cm^–1; ¹H NMR (400 MHz, CDCl₃) 7.51 (d, J = 7.6 Hz, 1H), 7.41 (m, 3H), 7.33 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 3.82 (s, 2H), 3.64 (s, 3H), 3.09 (m, 1H), 1.33 (d, J = 7.2 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.6, 166.0, 151.0, 139.4, 138.0, 134.8, 129.0, 128.4, 127.5, 118.6, 51.8, 41.9, 36.0, 22.6; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₇H₁₉NO₂Na⁺ 292.1308; Found: 292.1309.

Methyl 2-(3,6-Diphenylpyridin-2-yl)acetate (10d)

Following general procedure B, pyridine 10b was synthesized as a light-yellow oil (69 mg, 59% yield). TLC (30% EtOAc in hexane), R_f: 0.25 (CAM); IR film 1734, 1456, 1433, 1337, 1230, 1200, 1163, 1153, 1007, 708 cm^–1; ¹H NMR (400 MHz, CDCl₃) 8.06 (s, 1H), 7.72, (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.48–7.36 (m, 10H), 3.93 (s, 2H), 3.67 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.6, 155.8, 151.9, 139.1, 138.9, 138.4, 134.0, 129.0, 128.9, 128.7, 128.6, 127.8, 126.9, 118.7, 52.0, 42.1; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₁₈NO₂⁺ 304.1332; Found 304.1331.

Methyl 2-(5-Methyl-3-phenylpyridin-2-yl)acetate and Methyl 2-(5-methyl-4-phenylpyridin-2-yl)acetate (10e/11e)

Following general procedure B, pyridines 10e and 11e were synthesized as a light-yellow oil (18 mg, 50% yield). The resulting isomers were inseparable by flash column chromatography and are characterized as a mixture. TLC (10% EtOAc in hexane), R_f: 0.60 (CAM); IR film 1736, 1435, 1335, 1161, 1007, 775 cm^–1; ¹H NMR (400 MHz, CDCl₃) 8.45 (s, 1H), 8.42 (s, 1H), 7.45–7.32 (m, 5H), 7.38–7.26 (m, 5H), 3.86 (s, 2H), 3.80 (s, 2H), 2.36 (s, 3H), 2.26 (s, 3H);¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.6, 171.2, 151.7, 150.9, 149.9, 149.1, 148.9, 130.1, 138.92, 138.4, 137.2, 131.6, 129.2, 128.9, 128.5, 128.5, 128.4, 128.0, 127.7, 124.1, 52. 2, 52.0, 43.2, 41.1, 18.0, 16.9; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₅H₁₅NO₂H⁺ 242.1175; Found 242.1174.

Methyl 2-(3,5-Diphenylpyridin-2-yl)acetate (10f/11f)

Following general procedure B, pyridines 10f and 11f were synthesized as a light-yellow oil (35 mg, 56% yield). The resulting isomers were inseparable by flash column chromatography and are characterized as a mixture. TLC (30% EtOAc in hexane), R_f: 0.25 (CAM); IR film 1732, 1447, 1435, 1240, 1209, 1157, 1043, 764 cm^–1; ¹H NMR (400 MHz, CDCl₃) 8.59 (s, 1H), 7.35 (s, 1H), 7.26 (m, 4H), 7.15 (m, 4H), 3.95 (s, 2H), 3.77 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.1, 153.2, 150.7, 148.4, 138.5, 137.4, 134.4, 129.8, 129.3, 128.2, 128.2, 127.9, 127.3, 124.7, 52.2, 43.4; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₁₈NO₂⁺ 304.1332; Found 304.1331.

Methyl 2-(3,5,6-Triphenylpyridin-2-yl)acetate and methyl 2-(4,5,6-triphenylpyridin-2-yl)acetate (10g/11g)

Following general procedure B, pyridines 10g and 11g were synthesized as a light-yellow oil (27 mg, 39% yield). A small portion of 10g was obtained for analytical purposes and ¹H NMR data below is for isomerically pure 10g; ¹³C{¹H} NMR data was obtained using a mixture of isomers 10g and 11g. TLC (10% EtOAc in hexane), R_f: 0.50 (CAM); IR film 1738, 1537, 1260, 1163, 757 cm^–1; ¹H NMR of isomerically pure 10g (400 MHz, CDCl₃) 7.35 (s, 1H), 7.25 (m, 3H), 7.19 (m, 5H), 7.06 (m, 5H), 6.87 (m, 2H), 4.01 (s, 2H), 3.77 (s, 3H); ¹³C{¹H} NMR of isomers 10g and 11g (100 MHz, CDCl₃) δ 171.3, 158.1, 152.8, 150.4, 140.6, 139.3, 137.6, 132.9, 131.4, 130.0, 129.3, 127.8, 127.7, 127.4, 127.3, 126.6, 123.7, 52.1, 43.6; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₆H₂₁NO₂Na⁺ 402.1464; Found 402.1465.

Methyl 2-(3-Phenyl-5,6,7,8-tetrahydroquinolin-2-yl)acetate (10h)

Following general procedure B, pyridine 10h was synthesized as a light-yellow oil (19 mg, 68% yield). TLC (20% EtOAc in hexane), R_f: 0.30 (CAM); IR film 1736, 1433, 1155, 702 cm^–1; ¹H NMR (400 MHz, CDCl₃) 7.40–7.28 (m, 5H), 7.25 (s, 1H), 3.78 (s, 2H), 3.63 (s, 3H), 2.95 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 1.93–1.91 (m, 2H), 1.85–1.82 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.8, 156.2, 148.7, 139.5, 138.4, 135.0, 130.8, 129.0, 128.4, 127.5, 51.9, 41.4, 32.2, 28.4, 23.1, 22.7; HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₈H₁₉NO₂Na⁺ 282.1488; Found 282.1490.

Methyl 2-Methylbenzo[f]quinoline-5-carboxylate (13)

A dry vial was charged with oxazinone 8e (50 mg, 0.27 mmol, 1 equiv) and 2-ethylyl-benzaldehyde (12) (43 mgs, 0.33 mmol, 1.2 equiv), and dissolved in PhMe (1 mL). The resulting solution was heated to 120 °C using an aluminum heating block and stirred for 72 h. The reaction mixture was cooled to rt, concentrated in vacuo, and the resulting material was purified by flash column chromatography on silica gel (gradient elution: 0% to 80% EtOAc) to yield pyridine 13 as an amorphous yellow solid (28 mg, 39% yield). TLC: 40% EtOAC in hexanes, R_f. 0.40 (KMnO₄); IR (film) 1724, 1238, 1209, 1198, 1172, 1024, 808, 752 cm^–1; ¹H NMR (400 MHz, CDCl₃) 8.92 (s, 1H), 8.75 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 6.4 Hz, 1H), 7.70 (t, J = 6.4 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 168.3, 151.5, 143.1, 131.4, 130.5, 130.2, 130.2, 130.1, 129.5, 128.5, 127.6, 125.4, 122.5, 52.6, 19.0; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₆H₁₃NO₂H⁺ 252.1019; Found 252.1019.

Methyl 2-(5-Methyl-3-(2-nitrophenyl)pyridin-2-yl)acetate and Methyl 2-(5-methyl-4-(2-nitrophenyl)pyridin-2-yl)acetate (16a and 16b)

A dry vial was charged with oxazinone 8e (150 mg, 1 equiv) and 1-ethynyl-2-nitrobenzene (15) (142 mg, 1.5 equiv) and dissolved in PhMe (1.5 mL, 0.54M). The resulting solution was heated to 120 °C using an aluminum heating block and stirred for 96 h. The reaction mixture was cooled to rt and concentrated in vacuo. ¹H NMR analysis of the resulting unpurified reaction mixture revealed a 3:2 mixture of pyridine isomers 16a and 16b. The resulting material was purified by flask column chromatography on silica gel (gradient elution: 5 to 80% EtOAc in hexanes) to yield 16a and 16b as a mixture of isomers as a brown oil (88 mg, 37% yield). The structure of 16a was confirmed as the major isomer by NOE. The isomers proved inseparable by chromatography and data is reported on a mixture of isomers 16a and 16b. TLC (40% EtOAc in hexane), R_f: 0.30 (KMnO₄); IR (film) 1772, 1734, 1653, 1506, 951 cm^–1; ¹H NMR 16a, major isomer (400 MHz, CDCl₃) 8.46 (d, J = 1.6, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 7.40 (d, J = 6.8, 1H), 7.28 (s, 1H), 3.72 (d, J = 14.9, 1H), 3.61 (s, 3H), 3.53 (d, J = 16.0, 1H), 2.35 (s, 3H); ¹H NMR 16b, minor isomer (400 MHz, CDCl₃) 8.46 (d, J = 1.6, 1H), 8.11 (d, J = 7.6, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 7.07 (s, 1H), 3.86 (m, 2H), 3.73 (s, 3H), 2.07 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) 171.0, 170.9, 151.8, 150.4, 149.7, 149.0, 148.4, 146.6, 137.1, 133.9, 133.5, 133.3, 133.0, 132.9, 132.4, 131.5, 131.3, 129.4, 129.3, 129.3, 124.6, 124.5, 122.7, 52.2, 52.0, 43.2, 41.4, 17.9, 16.3. δ HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₅H₁₄N₂O₄Na⁺ 309.0846; Found 309.0846.

4-[(Trimethylsilyl)ethynyl]-1H-indole-2,3-dione (17)

A dry two neck flask was charged with 4-bromoisatin (2.00 g, 8.8 mmol) and dissolved in PhMe (56 mL), THF (56 mL), and NEt₃ (56 mL). The flask was fitted with an air condenser and was evacuated and backfilled with N₂ gas three times. Sequentially, PdCl₂(PPh₃)₂ (0.92 g, 1.32 mmol), TMS acetylene (1.75 mL, 12.3 mmol), and CuI (166 mg, 0.87 mmol) were added at rt. The reaction mixture was evacuated and backfilled with N₂ two additional times and the reaction mixture was heated to 50 °C using an aluminum heating block. After heating for 2 h, the reaction was cooled to rt, concentrated in vacuo, and partitioned between 20 mL of EtOAc and an equal volume of sat. aqueous NH₄Cl. The organic layer was removed, and the aqueous layer was extracted with additional EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (gradient elution: 10% EtOAc to 100% EtOAc in hexanes) to afford 17 (1.64 g, 77% yield) as an amorphous orange solid. Isatin 17 proved sensitive and prone to degradation. TLC (40% EtOAc in hexane), R_f: 0.50 (KMnO₄); IR (film) 3150, 1736, 1586, 1246, 841 cm^–1; ¹H NMR (400 MHz, CDCl₃) 8.97 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.13 (dd, J₁= 0.8 Hz, J₂ = 8.0 Hz, 1H), 6.95 (dd, J₁= 0.8 Hz, J₂ = 8.0 Hz, 1H) 0.31 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 181.1, 159.4, 149.4, 137.6, 128.0, 121.8, 117.9, 112.5, 104.7, 100.0, −0.4. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₃H₁₃NO₂SiNa⁺ 266.0608; Found 266.0608.

Methyl-9-Methyl-5-oxo-10-(trimethylsilyl)-4,5-dihydroindolo[4,3-fg]quinoline-6-carboxylate (18)

A dry vial was charged with TMS alkyne 17 (20 mg, 0.08 mmol) and oxazinone 8e (60 mg, 0.08 mmol). The flask was flushed with N₂ gas for five min and the starting materials dissolved in PhMe (150 μL, 0.5M). The reaction was heated for 16 h at 120 °C using an aluminum heating block. After cooling to rt, the reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography on silica gel (gradient elution: 10% EtOAc in hexanes to 100% EtOAc). The resulting product 18 was obtained as an orange solid (23 mg, 78% yield). Mp: 230–235 °C; TLC (60% EtOAc in hexane), R_f. 0.5 (CAM); IR (film) 1740, 1702, 1653, 1630, 1270, 1226, 1067, 847 cm^–1; ¹H NMR (400 MHz, CDCl₃) 8.78 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.55 (m, 1H), 7.07 (d, J = 7.2 Hz, 1H), 5.30 (s, 1H), 4.20 (d, J = 4.4 Hz, 3H), 2.75 (s, 3H), 0.46 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 194.9, 167.3, 167.1, 151.4, 146.1, 144.17, 141.6, 137.5, 133.8, 132.8, 127.8, 127.6, 123.4, 122.2, 122.0, 107.9, 53.3, 22.5, 2.8. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₀N₂O₃SiH⁺ 365.1316; Found 365.1315.

9-Methylindolo[4,3-fg]20uinoline-5(4H)-one (20)

A dry vial was charged with 18 (170 mg, 0.467 mmol) and dissolved in MeOH (2 mL) and H₂O (2 mL). To this solution was added LiOH (98 mg, 2.33 mmol), and the vial was heated to 50 °C for 72 h using an aluminum heating block. The reaction mixture was diluted with 0.1 M HCl (25 mL) and the resulting precipitated solids were removed by vacuum filtration to give carboxylic acid 19 (40 mg, 0.14 mmol) as a red solid, which was used directly in the following reaction without further purification. The material (19) thus obtained was transferred to a vial, dissolved in dimethylacetamide (100 μL) and Cu₂O (0.35 mg, 0.0025 mmol) and TMEDA (1 μL, 0.005 mmol) were added. The vial was sealed with a teflon cap and the reaction vessel was placed in an aluminum heating block set to 140 °C. After heating for 48 h, the reaction mixture was cooled to rt, and concentrated in vacuo. The resulting residue was purified via flash column chromatography (gradient elution: 0 to 100% EtOAc in hexanes) to give xylanigripone A (20) as a yellow oil (9 mg, 31% yield over two steps from 18). TLC (60% EtOAc in hexane), R_f. 0.5 (CAM); ¹H NMR (400 MHz, CDCl₃): 8.97 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.67 (t, J = 8.4 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 2.67 (s, 3H). ¹H NMR (400 MHz, pyridine-d₅): 12.38 (s, 1H), 9.00 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 2.44 (s, 3H). ¹³C{¹H} NMR (100 MHz, pyridine-d₅): 170.1, 152.8, 148.4, 140.3, 134.0, 131.7, 130.5, 129.7, 128.3, 127.9, 127.3, 116.3, 107.8, 19.1. ¹H and ¹³C NMR spectroscopic data for 20 are in agreement with published spectra from the isolation work³⁰ and prior synthesis efforts.^34,35

Data Availability Statement

The data underlying this study are available in the published article and the Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c02389.

• Supporting Information including ¹H and ¹³C NMR spectra for all new compounds (PDF)

The authors declare no competing financial interest.