Synthetic Approach to Chromone and Flavonoid Piperidine Alkaloids

Abstract

Despite the enormous importance of chromone and flavonoid piperidine alkaloids, a general method for their synthesis has not been described. Accordingly, from simple tetrahydro-3-pyridinemethanols (A) and phenol derivatives (B), a synthetic approach to chromone and flavonoid piperidine alkaloids is presented. The access to a novel chromone and flavonoid alkaloid precursors 4-(2-hydroxyphenyl)-3-methylenepiperidines (C) is achieved in only two steps: Mitsunobu reaction followed by an intramolecular C–H phenolization via an aromatic Claisen rearrangement of the respective Mitsunobu adducts (D). Consequently, the simultaneous installation of the functionalized phenol group and the exo-methylene group within the piperidine skeleton, permits, not only the easy construction of the chromone or flavonoid cores but also the simultaneous installation of the hydroxyl group with the required cis-orientation. Additionally, the synthetic utility of this novel approach is showcased in the formal synthesis of flavopiridol, rohitukine, and their N-Moc analogues.

Introduction

Chromone piperidine alkaloids¹ belong to a selected class of natural products isolated from Maliaceae^2a,2b and Rubiaceae families,^2c and widely used in traditional medicine,³ especially in the Indian folk medicine.⁴ Since they have shown potent anticancer activity,⁵ scientists have designed flavonoid piperidine alkaloids, a type of synthetic alkaloids, that with the simple structural modification of changing a methyl group by an aryl group (e.g., rohitukine and flavopiridol; Figure 1), the anticancer activity is considerably increased.⁶ Presumably, the high anticancer activity of flavopiridol, is attributed to the chlorine atom,^6,7 which enhance the interactions with the active site of CDK2, which induces cell cycle arrest in many cancer cells.⁷

Figure 1.

Rohitukine, flavopiridol and dysoline as representative examples of chromone and flavonoid alkaloids.

Unlike general classification of alkaloids, which is based on the nitrogen skeleton, the chromone and flavonoid alkaloids are classified on the basis of their 5,7-dihydroxy-chromone (noreugenin) moiety linked to the piperidine ring.^1a

Accordingly, rohitukine and dysoline, which possess a methyl group at C2 position, are isomeric chromones at C8–C4′ and C6–C4′, respectively; while the flavopiridol, with the aryl group at C2-position, is a C8–C4′ synthetic flavonoid alkaloid (Figure 1). Additionally, another relevant structural feature is the cis-oriented hydroxyl group at C3′ position.

Based on this brief structural analysis, it is clear that the major synthetic challenge to prepare these very important alkaloids (and analogues thereof), is the selective installation of the polyhydroxy phenol group at C4′ position and the C3′-hydroxyl group, both cis-oriented.

In this regard, the condensation of 1-methyl-4-piperidinone 1 with 1,3,5-trimethoxybenzene 2 to unsaturated piperidine 3 followed by hydroboration, oxidation and reduction processes to set the C3′ hydroxyl group, is the standard synthesis procedure for C8–C4′ isomers (eq 1; Scheme 1).⁸ In contrast, an elegant asymmetric synthesis of chromone alkaloid dysoline (C6–C4′ isomer) was reported by Coffin and Ready,⁹ in which the construction of the chromone core was achieved by using the Danheiser benzannulation¹⁰ reaction between protected silyl ynol ether 4 and diazo ketone 5 (eq 2; Scheme 1). Although the two strategies are complementary, there are still shortcomings either on the need of preparing analogues for medicinal chemistry or with the long and complex routes for preparing precursors, such as ynol ether 4 and diazo keto 5.

Scheme 1. Existing Approaches for Chromone/Flavonoid Piperidine Alkaloids (eqs 1 and 2); Current Approach (eq 3).

In this sense, a simple approach that enables rapid and modular access to either known or novel chromone/flavonoid piperidine alkaloids was envisioned based on an intramolecular C–H phenolization of tetrahydro-3-pyridinemethanol derivatives (7) to 4-(2-hydroxyphenyl)-3-methylenepiperidines (6) via an aromatic Claisen rearrangement reaction,¹¹ followed by the construction of flavone/chromone core from the phenol group and the hydroxyl group with the required relative cis configuration from the concomitant exocyclic double-bond (eq 3; Scheme 1).

Results and Discussion

The N-benzylated tetrahydro-3-pyridimethanol 8a(12) and sesamol were selected as suitable partners for the preparation of the aromatic Claisen precursor 9 in good chemical yield through a standard Mitsunobu reaction conditions [(diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh₃)] (Scheme 2).¹³

Scheme 2. Preparation of the Aromatic Claisen Precursor 9.

Once precursor 9 was prepared, thermal optimal reaction conditions for the aromatic Claisen rearrangement were investigated (Table 1; entries 1–10). The precursor 9 was dissolved and loaded inside a tube, which was sealed and submerged in an oil bath. Heating at 180 °C in CH₃CN, the entire starting material 9 was transformed into adduct 10 in 180 min in a good chemical yield (entry 1). Increasing the temperature by 10 °C was enough to complete the rearrangement in 90 min with a better yield (entry 2). However, when increasing the temperature another 10 °C, the consumption of 9 occurred in only 40 min but at a lower yield (entry 3). Switching solvent to EtOAc and toluene gave similar results to those obtained with CH₃CN (entries 4, 5, and 6); however, the lowest chemical yield was obtained with DMF (entry 7).

Table 1. Aromatic Claisen Rearrangement Optimization of 9.

entrya	solvent	temperature (°C)	time (min)	yield of 10 (%)b
1c	CH3CN	180	180	65
2c	CH3CN	190	90	76
3c	CH3CN	200	40	66
4c	EtOAc	200	40	68
5c	EtOAc	200	60	80
6c	PhMe	200	40	70
7c	DMF	200	40	58
8d	CH3CN	200	40	60
9d	PhMe	200	40	92
10d	EtOAc	200	40	48

^aReaction scale at 0.14 mmol of 9.

^bYields after purification.

^cConventional heating in an oil bath.

^dUnder microwave irradiation.

At this point we realized that the aromatic Claisen rearrangement is completed in 40 min at 200 °C with good chemical yields in all the solvents but DMF (entry 7); therefore, we decided to explore the rearrangement under microwave irradiation (entries 8–10). Accordingly, by using toluene as a solvent under microwave irradiation, the best chemical yield (92%) was obtained in 40 min (entry 9). Finally, it is important to remark that the regio-isomer 11 was not detected, which is consistent with the influence of the meta substituent in the regio-selectivity of this sigmatropic rearrangement.¹⁴

Once the optimal reaction conditions for the aromatic Claisen rearrangement were determined, we proceeded to extend the scope of this aromatic Claisen rearrangement to a series of Claisen precursors 12a–l containing both electron-withdrawing and electron-donating groups in all positions within the aromatic ring to, not only investigate the effect of the electronic nature of the substituents in the aromatic Claisen rearrangement but also to prepare potential valuable chromone and flavone precursors, which might be valuable for medicinal chemistry. Accordingly, 8a and 8b were transformed into 12a–k in moderate to good yields by reacting with DIAD and PPh₃ in THF at room temperature (eq 1; Scheme 3).¹³ The precursor 12l was prepared from 3-pyridinemethanol following the procedure depicted Scheme 3; eq 2.

Scheme 3. Synthesis of Claisen Precursors 12a–l.

Then, the aromatic Claisen rearrangement reaction conditions in toluene at 200 °C in a microwave reactor for 40 min were applied to 12a–l (Scheme 4). As expected, the more activated the aromatic rings, the higher chemical yields are obtained, conversely with deactivated aromatic rings, negligible reactivity is observed. For the case R = H (12a), low chemical yield of 13a was obtained; albeit a small amount of the starting material was recovered and reused (∼20% of 12a) to increase the yield up to 41%. On the other hand, when the aromatic ring bears electron-donating substituents such as 9, 12b, 12d, 12e, 12g, 12k and 12l, good to high chemical yields of their respective Claisen adducts (10, 13b, 13d, 13e, 13g/13gg, 13k and 13l) were obtained.

Scheme 4. Intramolecular C–H Phenolization via Aromatic Claisen Rearrangement.

The combined chemical yield for the Claisen rearrangement of 12g → 13g plus 13gg is 79% since both derive from the same Claisen adduct (not shown), from which, Boc protecting group is either removed (13g) or retained in the form of an oxazolidinone (13gg). In contrast, electron-withdrawing groups (12f, 12h and 12i), inhibit the formation of the Claisen adducts (13f, 13h and 13i). While halogens like iodide (12c) did not provide the respective Claisen adduct (13c), fluoride (12j) substituent behaves similar to simple phenyl group, and Claisen adduct 13j is obtained in moderate yield. Other substituents at the nitrogen atom rather than Bn or p-methoxybenzyl (PMB), such as the methyl group, do not affect the Claisen rearrangement when the aromatic ring is activated (13k and 13l).

Thereafter, we proceeded to prepare both flavone and chromone cores from the aromatic ring of 13e following reported protocols,^6,8 to then install the C3′ hydroxyl group with the cis relative configuration at the expense of the exocyclic double-bond via an oxidative double-bond cleavage followed by carbonyl group reduction. Accordingly, Friedel–Crafts acylation of 13e with acetic anhydride in the presence of BF₃·OEt₂ followed by base treatment with base (NaOH) afforded 14 quantitatively, which without further purification process, was subjected to either submitted, for one side to phenol acylation with 2-chlorobenzoyl chloride (15) to give 16, and for another side or treated with ethyl acetate to produce 18. Unlike arylated analogue 16, intermediate 18 was directly transformed into chromone 19 under acidic conditions with high overall yield (67% from 13e), while the aryl intermediate 16 had to be transformed into flavone derivative 17 in two sequential steps (see Scheme 5; above). Moreover, the installation of the hydroxyl group at C3′ position was not achieved as we planned. Attempts to cleavage the exocyclic double bond with ozone, OsO₄ or KMnO₄ were unsuccessful (Scheme 5; below). Although starting material 17 is consumed, the transient ketone intermediate (not shown) was neither isolated or trapped by subsequent reduction with NaBH₄ or L-selectride. Probably, the premature N-oxidation and further decomposition is faster than the expected double-bond oxidation, therefore, product 20 was not observed.

Scheme 5. Construction of Flavone and Chromone Moiety and Attempts to Install the cis-Hydroxyl Group at C3′ of the Piperidine Ring.

The problem was solved by designing novel chromone/flavone piperidine alkaloids containing a methyl carbamate (Moc) instead of a benzyl group (23 and 24, respectively), which led us to initiate a project for the search of novel flavopiridol and rohitukine analogs with anticancer activity.¹⁵ Thus, benzyl group of flavone 17 and chromone 19 was switched to Moc group (21 and 22, respectively) by using methyl chloroformate in the presence of NaHCO₃.¹² With the nitrogen atom deactivated, the installation of the cis-hydroxyl group at C3′ position was achieved in a sequential two-steps-one chromatographic purification: first ozone and dimethyl sulfide, then stereoselective carbonyl reduction with L-selectride to yield 23 and 24 in 68% and 50%, respectively. As expected, owing to both: the sterically bulky carbonyl group of the transitory ketone intermediates and the greater steric hindrance of the bulky hydride reagent, highly 3,4-cis-stereoselective reduction is observed; indeed, no traces of the trans diastereoisomer was detected (eq 1, Scheme 6). Additionally, we selected the N-Moc group because this group would also provide the N-Methyl group under reductive conditions.

Scheme 6. Synthesis of Flavopiridol-Moc and Rohitukine-Moc Analogues (23 and 24; eq 1); Formal Synthesis of Flavopiridol and Rohitukine (eq 2).

With these two novel flavopiridol-Moc and rohitukine-Moc analogues in hand, we tried to convert them into flavopiridol and rohitukine by exhaustive reduction of the N-Moc group into N-methyl with LiAlH₄; however, both the flavone and chromone core resulted to be more reactive than the Moc group, and a complex mixture of byproducts was obtained. In order to avoid struggling with the reactivity of the flavone and chromone core under strong reductive conditions, the synthesis of flavopiridol and rohitukine was achieved from N-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol (28).

Accordingly, N-Moc piperidine 25 was first methylated to 26 with CH₃I and NaH, and then, without further purification, was subjected to oxidative cleavage with ozone and S(Me)₂ in methanol at −60 °C followed by carbonyl reduction with L-selectride to obtain N-Moc-(2,4,6-trimethoxyphenyl)piperidin-3-ol 27 in 59% overall yield. Finally, the reduction of 27 under the same reaction conditions as for 23 and 24, afforded the synthetic intermediate 28, which its NMR data is consistent with the literature values.^8a,16 Finally, 28 could conduct to flavopiridol and rohitukine in only three or four steps following the reported procedures (eq 2, Scheme 6).^8a,8b

Conclusions

In summary, we have developed a modular approach that allows the installing of functionalized phenol groups at C4 position and a concomitant C3 exo-methylene group within the piperidine ring for the straightforward construction of the chromone/flavone skeleton and the C3-hydroxyl group with the required cis-relationship. The efficient aromatic Claisen rearrangement with electron-donating groups in the aromatic rings, such as OR, NHR and CH₃ groups, and also with moderated deactivating atoms like F, provides a novel synthetic approach to a number of novel chromone and flavonoid piperidine alkaloids that might be anticancer candidate drugs. In this regard, besides the synthetic application of this novel approach to the formal synthesis of flavopiridol and rohitukine, we also introduced two novel flavopiridol and rohitukine analogues which, along with others not reported herein, are in process of patent application and will be disclosed in due course.

Experimental Section

General Considerations

Commercially available reagents were purchased from Sigma-Aldrich and used without further purification. Unless otherwise noted, reactions were carried out under an inert argon atmosphere with dry solvents under anhydrous conditions. Reactions were monitored by thin-layer chromatography (TLC). Purifications of products were performed by column chromatography using silica gel (230–400 mesh). Microwave synthesis was performed in the microwave reactor CEM Discover System (model 908005) in a sealed vessel. Claisen arrangement reactions were also carried out in a sealed tube and heated in an oil bath at 200 °C. The temperature was regulated using a digital contact thermometer. NMR spectra were obtained on Bruker-500 (500 MHz) spectrometer using TMS as an internal reference for ¹H (0.00 ppm) and CDCl₃ for ¹³C (77.16 ppm) unless otherwise noted. Chemical shifts (δ) are stated in parts per million (ppm) and Hz for the coupling constants (J). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublets, td = triplet of doublets, qd = quartet of doublets. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. Melting points were not corrected and carried out on a Fisher-Scientific 12–144 melting point apparatus. High-resolution mass spectra-electron impact mode (HRMS-EI). High-resolution mass spectra-fast atom bombardment mode (HRMS-FAB). High-resolution mass spectra-electrospray ionization mode (HRMS-ESI).

General Procedure for the Preparation of (1,2,5,6-Tetrahydropyridin-3-yl)methanol 8a–8b

The tetrahydropyridines 8a and 8b were prepared using the procedure reported by Winkler et al.¹². The pyridine-3-methanol S1 (8.0 g, 73.31 mmol) was treated with the corresponding benzyl halide (76.97 mmol) in CH₂Cl₂ anhydrous (27.0 mL). The crude mixture was treated with NaBH₄ (6.10 g, 161.27 mmol) in MeOH (80.0 mL) at 0 °C for 12 h to obtain tetrahydropyridines 8a and 8b after quenching and purification processes.

(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)methanol (8a)

Following the general protocol, S1 and benzyl bromide (9.16 mL) were used to obtain 8a. The residue was purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (1:1) to obtain 13.70 g of 8a (92%) as a yellow oil. R_f = 0.16 (hexanes/EtOAc = 1:1); ¹H NMR (500 MHz, CDCl₃): δ 7.30 (m, 4H), 7.24 (m, 1H), 5.53 (m, 1H), 3.88 (s, 2H), 3.57 (s, 2H), 2.93 (apparent s, 2H), 2.50 (t, J = 5.8 Hz, 2H), 2.11 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 137.2 (C), 136.5 (C), 129.6 (2CH), 128.2 (2CH), 127.2 (CH), 120.4 (CH), 64.7 (CH₂), 62.9 (CH₂), 52.8 (CH₂), 49.6 (CH₂), 25.4 (CH₂).

(1-(4-Methoxybenzyl)-1,2,5,6-tetrahydropyridin-3-yl)methanol (8b)

Following the procedure, S1 and 4-methoxybenzyl chloride (10.4 mL) were used to obtain 8b. The residue was purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (1:1) to obtain 15.40 g of 8b (90%) as a yellow oil. R_f = 0.16 (hexanes/EtOAc = 1:1); ¹H NMR (500 MHz, CDCl₃): δ 7.24 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.55 (m, 1H), 3.90 (s, 2H), 3.78 (s, 3H), 3.52 (s, 2H), 2.92 (s, 2H), 2.49 (t, J = 5.8 Hz, 2H), 2.12 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 158.8 (C), 136.6 (C), 130.9 (2CH), 129.3 (C), 120.5 (CH), 113.6 (2CH), 64.9 (CH₂), 62.3 (CH₂), 55.3 (CH₃), 52.8 (CH₂), 49.5 (CH₂), 25.5 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₁₄H₁₉NO₂, 233.1416; found, 233.1434.

General Procedure for the Mitsunobu Reaction

To a solution of the tetrahydropyridine (0.25 mmol), triphenylphosphine (0.30 mmol), and the corresponding phenol (0.30 mmol) in THF anhydrous (3.0 mL) at 0 °C, under argon atmosphere, was added dropwise DIAD (0.30 mmol). The reaction mixture was stirred for 15 min at 0 °C and warmed to room temperature. Once the raw material was consumed, the solvent was removed under reduced pressure and the residue was treated with 1 N NaOH solution. The aqueous layer was extracted with EtOAc (3 × 10 mL), and the organic phase was dried with Na₂SO₄ and concentrated for its purification by column chromatography.

5-((Benzo[d][1,3]dioxol-5-yloxy) methyl)-1-benzyl-1,2,3,6-tetrahydropyridine (9)

Following the general protocol for the Mitsunobu reaction, 59.0 mg of 9 (73%) was obtained as a brown oil from 8a (50.0 mg, 0.25 mmol) and sesamol (41.0 mg, 0.30 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.10 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.32 (m, 4H), 7.25 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 6.30 (dd, J = 8.5, 2.5 Hz, 1H), 5.89 (s, 2H), 5.84 (m, 1H), 4.30 (s, 2H), 3.62 (s, 2H), 3.04 (s, 2H), 2.55 (t, J = 5.8 Hz, 2H), 2.20 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 154.4 (C), 148.3 (C), 141.8 (C), 138.3 (C), 132.7 (C), 129.3 (2CH), 128.4 (2CH), 127.2 (CH), 124.2 (CH), 108.0 (CH), 106.1 (CH), 101.2 (CH₂), 98.4 (CH), 71.9 (CH₂), 62.8 (CH₂), 53.5 (CH₂), 49.4 (CH₂), 25.9 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₂₀H₂₁NO₃ 323.1521; found, 323.1513.

1-Benzyl-5-(phenoxymethyl)-1,2,3,6-tetrahydropyridine (12a)

Following the general protocol, 8a (50.0 mg, 0.25 mmol) and phenol (30.0 mg, 0.30 mmol) were used to obtain 12a. The residue was purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1) to obtain 41.9 mg of 12a (60%) as a yellow oil. R_f= 0.10 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.32 (m, 4H), 7.25 (m, 3H), 6.90 (m, 3H), 5.87 (m, 1H), 4.37 (s, 2H), 3.62 (s, 2H), 3.07 (apparent q, J = 2.5 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.21 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 158.9 (C), 138.3 (C), 132.7 (C), 129.5 (2CH), 129.3 (2CH), 128.4 (2CH), 127.2 (CH), 124.1 (CH), 120.9 (CH), 114.8 (2CH), 70.8 (CH₂), 62.8 (CH₂), 53.6 (CH₂), 49.4 (CH₂), 25.9 (CH₂). HRMS-EI m/z: [M] ⁺ calcd for C₁₉H₂₁NO 279.1623; found, 279.1627.

1-Benzyl-5-((4-methoxyphenoxy) methyl)-1,2,3,6-tetrahydropyridine (12b)

Following the protocol, 48.7 mg of 12b (63%) was obtained from 8a (50.0 mg, 0.25 mmol) and 4-methoxyphenol (40.0 mg, 0.30 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1) to give 12b as a yellow oil. R_f= 0.10 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.36–7.30 (m, 4H), 7.25 (m, 1H), 6.81 (m, 4H), 5.85 (m, 1H), 4.33 (s, 2H), 3.75 (s, 3H), 3.62 (s, 2H), 3.06 (m, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.20 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 154.0 (C), 153.1 (C), 138.4 (C), 132.9 (C), 129.3 (2CH), 128.4 (2CH), 127.2 (CH), 124.0 (CH), 115.8 (2CH), 114.7 (2CH), 71.6 (CH₂), 62.8 (CH₂), 55.8 (CH₃), 53.6 (CH₂), 49.4 (CH₂), 25.9 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₂₀H₂₄NO₂ 310.1807; found, 310.1808.

1-Benzyl-5-((2-iodophenoxy)methyl)-1,2,3,6-tetrahydropyridine (12c)

Following the protocol, 81.0 mg of 12c (80%) was obtained as a yellow oil from 8a (50.0 mg, 0.25 mmol) and 2-iodophenol (66.0 mg, 0.30 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). The NMR data agree with those reported by Mayrargue et al.¹⁷R_f= 0.06 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.74 (d, J = 8.0 Hz, 1H), 7.36 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 7.8 Hz, 1H), 5.91 (m, 1H), 4.43 (s, 2H), 3.64 (s, 2H), 3.12 (m, 2H), 2.60 (t, J = 5.8 Hz, 2H), 2.23 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 157.3 (C), 139.5 (CH), 138.3 (C), 132.1 (C), 129.5 (CH), 129.4 (2CH), 128.4 (2CH), 127.2 (CH), 123.9 (CH), 122.7 (CH), 112.5 (CH), 86.9 (C), 71.8 (CH₂), 62.9 (CH₂), 53.4 (CH₂), 49.6 (CH₂), 25.9 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₁₉H₂₀INO 405.0590; found, 405.0593.

1-Benzyl-5-((2,3-dimethylphenoxy) methyl)-1,2,3,6-tetrahydropyridine (12d)

Following the protocol, 0.18 g of 12d (45%) was obtained as a yellow oil from 8a (0.26 g, 1.27 mmol) and 2,3-dimethylphenol (0.19 g, 1.52 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.12 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.36–7.31 (m, 4H), 7.25 (m, 1H), 7.01 (apparent t, J = 7.8 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 5.86 (m, 1H), 4.35 (s, 2H), 3.62 (s, 2H), 3.07 (s, 2H), 2.58 (t, J = 5.8 Hz, 2H), 2.25 (s, 3H), 2.22 (br, 2H), 2.10 (s, 3H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 156.7 (C), 138.2 (C), 138.0 (C), 133.0 (C), 129.3 (2CH), 128.3 (2CH), 127.2 (CH), 125.8 (CH), 125.4 (C), 123.3 (CH), 122.4 (CH), 109.1 (CH), 71.0 (CH₂), 62.9 (CH₂), 53.4 (CH₂), 49.6 (CH₂), 25.8 (CH₂), 20.2 (CH₃), 11.8 (CH₃). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₆NO 308.2014; found, 308.2018.

1-Benzyl-5-((3,5-dimethoxyphenoxy)methyl)-1,2,3,6-tetrahydropyridine (12e)

Following the protocol, 0.28 g of 12e (60%) was obtained as a yellow oil from 8a (0.28 g, 1.38 mmol) and 0.26 g of 3,5-dimethoxyphenol (1.66 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.10 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.36 (m, 2H), 7.31 (m, 2H), 7.25 (m, 1H), 6.08 (m, 3H), 5.87 (m, 1H), 4.33 (s, 2H), 3.74 (s, 6H), 3.62 (s, 2H), 3.06 (m, 2H), 2.57 (t, J = 5.8 Hz, 2H), 2.20 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 161.5 (2C), 160.8 (C), 138.3 (C), 132.5 (C), 129.3 (2CH), 128.3 (2CH), 127.2 (CH), 124.3 (CH), 93.6 (2CH), 93.1 (CH), 70.9 (CH₂), 62.8 (CH₂), 55.4 (2CH₃), 53.6 (CH₂), 49.3 (CH₂), 25.9 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₂₁H₂₆NO₃, 340.1913; found, 340.1889.

4-((1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)benzonitrile (12f)

Following the protocol, 0.23 g of 12f (70%) was obtained as a yellow oil from 8a (0.22 g, 1.08 mmol) and 4-cyanophenol (0.15 g, 1.30 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.06 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.55 (d, J = 8.5 Hz, 2H), 7.33 (m, 4H), 7.25 (m, 1H), 6.92 (d, J = 8.5 Hz, 2H), 5.88 (m, 1H), 4.42 (s, 2H), 3.62 (s, 2H), 3.03 (br, 2H), 2.57 (t, J = 5.8 Hz, 2H), 2.22 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 162.1 (C), 138.1 (C), 134.0 (2CH), 131.6 (C), 129.2 (2CH), 128.4 (2CH), 127.2 (CH), 125.2 (CH), 119.3 (C), 115.5 (2CH), 104.1 (C), 71.1 (CH₂), 62.7 (CH₂), 53.3 (CH₂), 49.3 (CH₂), 25.9 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₂₀H₂₀N₂O 304.1576; found, 304.1580.

tert-Butyl-(2-((1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)phenyl)carbamate (12g)

Following the protocol, 0.18 g of 12g (44%) was obtained as a yellow oil from 8a (0.21 g, 1.03 mmol) and 0.26 g of N-Boc-2-aminophenol (1.24 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.06 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 8.08 (br, 1H), 7.32 (m, 4H), 7.26 (m, 1H), 7.05 (br, 1H), 6.92 (m, 2H), 6.83 (m, 1H), 5.87 (m, 1H), 4.42 (s, 2H), 3.63 (s, 2H), 3.06 (apparent q, J = 2.3 Hz, 2H), 2.57 (t, J = 5.8 Hz, 2H), 2.22 (br, 2H), 1.54 (s, 9H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 152.9 (C), 146.7 (C), 138.0 (C), 132.2 (C), 129.3 (2CH), 128.4 (2CH), 128.3 (CH), 127.3 (CH), 124.7 (CH), 122.3 (CH), 121.3 (CH), 118.2 (CH), 111.4 (CH), 80.4 (C), 71.4 (CH₂), 62.8 (CH₂), 53.5 (CH₂), 49.2 (CH₂), 28.5 (3CH₃), 25.8 (CH₂). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₁N₂O₃ 395.2335; found, 395.2331.

4-((1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)benzaldehyde (12h)

Following the protocol, 43.0 mg of 12h (56%) was obtained as a yellow oil from 8a (50.0 mg, 0.25 mmol) and 4-hydroxybenzaldehyde (36.6 mg, 0.30 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.04 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 9.88 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.32 (m, 4H), 7.25 (m, 1H), 6.99 (d, J = 8.5 Hz, 2H), 5.91 (m, 1H), 4.47 (s, 2H), 3.63 (s, 2H), 3.06 (m, 2H), 2.58 (t, J = 5.8 Hz, 2H), 2.23 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 191.0 (C), 164.0 (C), 138.2 (C), 132.1 (2CH), 131.8 (C), 130.1 (C), 129.3 (2CH), 128.4 (2CH), 127.3 (CH), 125.1 (CH), 115.1 (2CH), 71.1 (CH₂), 62.8 (CH₂), 53.4 (CH₂), 49.4 (CH₂), 25.9 (CH₂). HRMS (ESI-TOF) m/z: [M + H] ⁺ calcd for C₂₀H₂₂NO₂ 308.1651; found, 308.1648.

1-Benzyl-5-((2-nitrophenoxy) methyl)-1,2,3,6-tetrahydropyridine (12i)

Following the protocol, 0.25 g of 12i (61%) was obtained as a yellow oil from 8a (0.26 g, 1.27 mmol) and 2-nitrophenol (0.21 g, 1.52 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.06 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.82 (dd, J = 8.3, 1.7 Hz, 1H), 7.49 (td, J = 8.3 Hz, 1.5 Hz, 1H), 7.33 (m, 4H), 7.25 (m, 1H), 7.05 (d, J = 8.5 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 5.92 (m, 1H), 4.52 (s, 2H), 3.63 (s, 2H), 3.07 (m, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.22 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 152.1 (C), 139.9 (C), 138.1 (C), 134.1 (CH), 131.3 (C), 129.3 (2CH), 128.4 (2CH), 127.2 (CH), 125.7 (CH), 124.9 (CH), 120.4 (CH), 114.8 (CH), 72.1 (CH₂), 62.7 (CH₂), 53.2 (CH₂), 49.3 (CH₂), 25.8 (CH₂). HRMS (ESI-TOF) m/z: [M + H] ⁺ calcd for C₁₉H₂₁N₂O₃ 325.1552; found, 325.1545.

1-Benzyl-5-((2-fluorophenoxy)methyl)-1,2,3,6-tetrahydropyridine (12j)

Following the protocol, 86.0 mg of 12j (59%) was obtained as a yellow oil from 8a (0.1 g, 0.49 mmol) and 2-fluorophenol (65.9 mg, 0.59 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.12 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.36–7.30 (m, 4H), 7.25 (m, 1H), 7.07–7.00 (m, 2H), 6.94 (td, J = 8.3, 1.7 Hz, 1H), 6.88 (m, 1H), 5.88 (m, 1H), 4.45 (s, 2H), 3.62 (s, 2H), 3.08 (m, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.20 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 153.0 (d, J = 244.1 Hz, CF), 146.8 (d, J = 10.5 Hz, C), 138.2 (C), 132.3 (C), 129.3 (2CH), 128.3 (2CH), 127.2 (CH), 124.6 (CH), 124.3 (d, J = 4.0 Hz, CH), 121.4 (d, J = 6.8 Hz, CH), 116.4 (d, J = 18.4 Hz, CH), 115.8 (d, J = 1.9 Hz, CH), 72.3 (CH₂), 62.7 (CH₂), 53.4 (CH₂), 49.3 (CH₂), 25.8 (CH₂). HRMS (ESI-TOF) m/z: [M + H] ⁺ calcd for C₁₉H₂₁FNO 298.1607; found, 298.1598.

5-((3,5-Dimethoxyphenoxy)methyl)-1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridine (12k)

Following the general protocol for the Mitsunobu reaction, 0.71 g of 12k (50%) was obtained as a yellow oil from 8b (0.9 g, 3.86 mmol) and 3,5-dimethoxyphenol (0.71 g, 4.63 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (3:1). R_f= 0.04 (hexanes/EtOAc = 3:2); ¹H NMR (500 MHz, CDCl₃): δ 7.25 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.08 (br, 3H), 5.86 (m, 1H), 4.33 (d, J = 2.0 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 6H), 3.55 (s, 2H), 3.03 (m, 2H), 2.54 (t, J = 5.8 Hz, 2H), 2.20 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 161.6 (2C), 160.9 (C), 158.9 (C), 132.6 (C), 130.5 (2CH), 130.3 (C), 124.4 (CH), 113.7 (2CH), 93.7 (2CH), 93.2 (CH), 71.0 (CH₂), 62.1 (CH₂), 55.4 (2CH₃), 55.4 (CH₃), 53.5 (CH₂), 49.2 (CH₂), 25.9 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₂₂H₂₈NO₄, 370.2018; found, 370.2010.

Synthesis of Precursor 12l

3-((3,5-Dimethoxyphenoxy)methyl)pyridine (S2)

To a solution of the 3-pyridinemethanol S1 (5.0 g, 45.82 mmol), triphenylphosphine (14.42 g, 54.98 mmol), and the 3,5-dimethoxyphenol (8.48 g, 54.98 mmol) in THF anhydrous (92.0 mL) at 0 °C, under argon atmosphere, was added dropwise DIAD (10.83 mL, 54.98 mmol). The reaction mixture was stirred for 15 min at 0 °C, consequently, the reaction was stirred at room temperature, and monitored by TLC. Once the raw material was consumed, the solvent was removed under reduced pressure and the residue was treated with 1 N NaOH aqueous solution. The resulting mixture was extracted with EtOAc (3 × 20 mL), and the organic phase was dried with Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography with SiO₂ and eluted with EtOAc/MeOH (4:1) to give 9.90 g (88%) of S2 as a yellow oil. R_f = 0.5 (hexanes/EtOAc = 4:1); ¹H NMR (500 MHz, CDCl₃): δ 8.67 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 5.0, 1.5 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.32 (dd, J = 7.8, 4.8 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1H), 6.12 (m, 1H), 5.03 (s, 2H), 3.77 (s, 6H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 161.7 (2C), 160.4 (C), 149.6 (CH), 149.2 (CH), 135.4 (CH), 132.5 (C), 123.6 (CH), 93.8 (2CH), 93.6 (CH), 67.7 (CH₂), 55.5 (2CH₃). HRMS-FAB m/z: [M + H]⁺ calcd for C₁₄H₁₆NO₃, 246.1130; found, 246.1127.

5-((3,5-Dimethoxyphenoxy)methyl)-1-methyl-1,2,3,6-tetrahydropyridine(12l)

The compound 12l was obtained using the procedure reported by Mayrargue et al.¹⁷ To a stirred solution of pyridine S2 (1.95 g, 7.95 mmol) in dry dichloromethane (20 mL) was added dropwise iodomethane (0.59 mL, 9.54 mmol). The reaction mixture was stirred overnight at room temperature. Then, the white solid formed was filtered and washed with dichloromethane to afford the pyridinium salt S3 which was used without further purification in the next step. To a suspension of salt S3 (1.60 g, 4.29 mmol) in MeOH reagent grade (30 mL) cooled to 0 °C was added portion-wise of sodium borohydride (0.40 g, 10.73 mmol) over 20 min. Once the addition was complete, the mixture was allowed to stir overnight at room temperature. The methanol was removed under reduced pressure, the residue was treated with an aqueous solution of NaOH (15 mL, 1 N), and the aqueous phase was extracted with dichloromethane (3 × 15 mL). The combined organic phases were dried with Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by column chromatography with SiO₂ and eluted with EtOAc/Hexane (1:1) to give 1.25 g (60%) of 12l as a yellow oil. R_f = 0.06 (hexanes/EtOAc = 1:1); ¹H NMR (500 MHz, CDCl₃): δ 6.09 (s, 2H), 6.07 (s, 1H), 5.85 (m, 1H), 4.36 (s, 2H), 3.75 (s, 6H), 2.99 (br, 2H), 2.51 (td, J = 5.5, 1.7 Hz, 2H), 2.38 (s, 3H), 2.25 (br, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 161.5 (2C), 160.8 (C), 132.5 (C), 123.8 (CH), 93.6 (2CH), 93.1 (CH), 70.9 (CH₂), 55.4 (2CH₃), 55.3 (CH₂), 51.8 (CH₂), 46.0 (CH₃), 26.1 (CH₂). HRMS (ESI-TOF) m/z: [M + H] ⁺ calcd for C₁₅H₂₂NO₃ 264.1599; found, 264.1600.

Synthesis of 4-(2-hydroxyphenyl)-3-methylenepiperidines via a Claisen Rearrangement

Bath Oil Conditions (A)

To scale up the reaction, a 0.4 M solution of the corresponding allyl aryl ether (0.10–2.94 mmol) in reagent grade toluene was stirred at 200 °C in an oil bath. Once the raw material was consumed, the reaction was cooled to room temperature and concentrated under reduced pressure for purification by column chromatography.

Microwave Conditions (B)

A 0.4 M solution of the corresponding allyl aryl ether (0.10–0.16 mmol) in reagent grade toluene was placed in a microwave tube. The reaction mixture was heated to 200 °C for 40 min and concentrated under reduced pressure for purification by column chromatography.

6-(1-Benzyl-3-methylenepiperidin-4-yl)benzo[d][1,3]dioxol-5-ol (10)

Following the microwave (mw) protocol for the Claisen rearrangement, 35.7 mg of 10 (92%) was obtained as a brown oil from 9 (40.0 mg, 0.12 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1) as the solvent system. R_f= 0.06 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.34 (m, 4H), 7.28 (m, 1H), 6.61 (s, 1H), 6.41 (s, 1H), 5.88 (m, 2H), 4.86 (s, 1H), 4.46 (s, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.59 (d, J = 12.5 Hz, 1H), 3.48 (dd, J = 12.0, 2.0 Hz, 1H), 3.40 (m, 1H), 3.09 (d, J = 11.5 Hz, 1H), 2.82 (d, J = 12.5 Hz, 1H), 2.30 (td, J = 11.8, 3.0 Hz, 1H), 2.04 (qd, J = 12.3, 4.1 Hz, 1H), 1.81 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 148.6 (C), 146.5 (C), 145.6 (C), 141.3 (C), 137.2 (C), 129.6 (2CH), 128.4 (2CH), 127.4 (CH), 120.2 (C), 110.5 (CH₂), 108.4 (CH), 101.0 (CH₂), 99.1 (CH), 62.8 (CH₂), 60.6 (CH₂), 53.6 (CH₂), 42.3 (CH), 31.1 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₂₀H₂₁NO₃ 323.1521; found, 323.1516.

2-(1-Benzyl-3-methylenepiperidin-4-yl)phenol (13a)

Following the mw protocol, 12a (40.0 mg, 0.14 mmol) was used to obtain 13a. The residue was purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1) to obtain 13.6 mg of 13a (35%) as a yellow oil. R_f= 0.10 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.38–7.32 (m, 4H), 7.29 (m, 1H), 7.15 (m, 2H), 6.91 (apparent td, J = 7.5, 1.5 Hz, 1H), 6.85 (dd, J = 8.0, 1.5 Hz, 1H), 4.89 (s, 1H), 4.46 (s, 1H), 3.68 (d, J = 13.0 Hz, 1H), 3.61 (d, J = 13.0 Hz, 1H), 3.49 (m, 2H), 3.10 (apparent d, J = 11.0 Hz, 1H), 2.86 (d, J = 12.0 Hz, 1H), 2.33 (m, 1H), 2.15 (qd, J = 12.0, 4.4 Hz, 1H), 1.88 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 154.0 (C), 145.3 (C), 137.3 (C), 129.6 (2CH), 129.4 (CH), 128.5 (2CH), 128.1 (C), 128.1 (CH), 127.5 (CH), 120.9 (CH), 116.8 (CH), 110.8 (CH₂), 62.7 (CH₂), 60.4 (CH₂), 53.3 (CH₂), 43.1(CH), 30.7 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₁₉H₂₁NO 279.1623; found, 279.1616.

2-(1-Benzyl-3-methylenepiperidin-4-yl)-4-methoxyphenol (13b)

Following the mw protocol, 39.6 mg of 13b (80%) was obtained from 12b (50.0 mg, 0.16 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1) to give 13b as a yellow oil. R_f= 0.10 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.34 (m, 4H), 7.28 (m, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.71–6.67 (m, 2H), 4.86 (s, 1H), 4.43 (s, 1H), 3.74 (s, 3H), 3.66 (d, J = 13.0 Hz, 1H), 3.59 (d, J = 13.0 Hz, 1H), 3.48 (m, 2H), 3.09 (apparent d, J = 12.5 Hz, 1H), 2.84 (d, J = 13.0 Hz, 1H), 2.31 (td, J = 12.0, 3.0 Hz, 1H), 2.11 (qd, J = 12.3, 4.0 Hz, 1H), 1.85 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 153.9 (C), 147.9 (C), 145.6 (C), 137.7 (C), 129.5 (C), 129.4 (2CH), 128.4 (2CH), 127.4 (CH), 117.4 (CH), 114.9 (CH), 112.8 (CH), 110.4 (CH₂), 62.9 (CH₂), 60.7 (CH₂), 55.8 (CH₃), 53.5 (CH₂), 43.3 (CH), 31.0 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₂₀H₂₃NO₂ 309.1729; found, 309.1723.

6-(1-Menzyl-3-methylenepiperidin-4-yl)-2,3-dimethylphenol (13d)

Following the mw protocol, 53.5 mg of 13d (60%) was obtained as a yellow oil from 12d (90.0 mg, 0.29 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.12 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.37–7.32 (m, 4H), 7.28 (d, J = 6.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 4.90 (d, J = 2.0 Hz, 1H), 4.50 (s, 1H), 3.64 (d, J = 13.0 Hz, 1H), 3.59 (d, J = 13.0 Hz, 1H), 3.48 (dd, J = 12.0, 2.0 Hz, 1H), 3.37 (dd, J = 12.0, 5.0 Hz, 1H), 3.08 (d, J = 11.5 Hz, 1H), 2.82 (d, J = 12.0 Hz, 1H), 2.31 (m, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 2.13 (m, 1H), 1.86 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 151.9 (C), 145.5 (C), 137.8 (C), 136.6 (C), 129.4 (2CH), 128.4 (2CH), 127.3 (CH), 125.8 (CH), 125.1 (C), 123.9 (C), 122.2 (CH), 110.7 (CH₂), 62.8 (CH₂), 60.5 (CH₂), 53.6 (CH₂), 43.9 (CH), 30.9 (CH₂), 20.2 (CH₃), 12.0 (CH₃). HRMS-EI m/z: [M]⁺ calcd for C₂₁H₂₅NO 307.1936; found, 307.1935.

2-(1-Benzyl-3-methylenepiperidin-4-yl)-3,5-dimethoxyphenol (13e)

Following the mw protocol, 45.0 mg of 13e (88%) was obtained as an orange solid (mp = 171–173 °C) from 12e (0.05 g, 0.15 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.06 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.37–7.32 (m, 4H), 7.28 (d, J = 6.5 Hz, 1H), 6.13 (d, J = 2.0 Hz, 1H), 6.08 (d, J = 2.5 Hz, 1H), 4.90 (s, 1H), 4.73 (s, 1H), 4.09 (m, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.66 (d, J = 13.0 Hz, 1H), 3.58 (d, J = 13.0 Hz, 1H), 3.53 (d, J = 14.0 Hz, 1H), 3.00 (m, 1H), 2.86 (d, J = 13.0 Hz, 1H), 2.27 (td, J = 11.5, 3.5 Hz, 1H), 2.07 (m, 1H), 1.77 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 159.9 (C), 158.7 (C), 156.4 (C), 144.8 (C), 137.3 (C), 129.5 (2CH), 128.5 (2CH), 127.5 (CH), 110.5 (CH₂), 109.5 (C), 95.2 (CH), 91.6 (CH), 62.6 (CH₂), 59.7 (CH₂), 55.9 (CH₃), 55.4 (CH₃), 52.6 (CH₂), 35.1 (CH), 29.5 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₂₁H₂₅NO₃ 339.1834; found, 339.1829.

2-Amino-6-(1-benzyl-3-Methylenepiperidin-4-yl)phenol (13g)

Following the mw protocol, 13g and 13gg were obtained from 12g (34.0 mg, 0.09 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). 13g as a yellow oil (12.5 mg, 47%). R_f= 0.06 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.37–7.32 (m, 4H), 7.29 (m, 1H), 6.74 (t, J = 7.5 Hz, 1H), 6.68 (dd, J = 7.8, 1.5 Hz, 1H), 6.55 (dd, J = 7.3, 1.8 Hz, 1H), 4.91 (d, J = 2.0 Hz, 1H), 4.60 (d, J = 2.0 Hz, 1H), 3.67 (d, J = 13.0 Hz, 1H), 3.61 (d, J = 13.0 Hz, 1H), 3.52 (d, J = 13.0 Hz, 1H), 3.39 (dd, J = 11.3, 5.8 Hz, 1H), 3.09 (m, 1H), 2.86 (d, J = 12.5 Hz, 1H), 2.32 (td, J = 11.6, 3.3 Hz, 1H), 2.16 (qd, J = 11.8, 4.5 Hz, 1H), 1.90 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 145.0 (C), 142.3 (C), 137.2 (C), 135.9 (C), 129.5 (2CH), 128.5 (2CH), 128.3 (C), 127.5 (CH), 121.0 (CH), 119.7 (CH), 115.3 (CH), 111.0 (CH₂), 62.6 (CH₂), 60.0 (CH₂), 52.9 (CH₂), 44.3 (CH), 30.3 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₁₉H₂₂N₂O, 294.1732; found, 294.1732.

7-(1-Benzyl-3-methylenepiperidin-4-yl)benzo[d]oxazol-2(3H)-one (13gg)

As a yellow oil (9.2 mg, 32%). R_f= 0.10 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.39–7.32 (m, 4H), 7.28 (m, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.93 (dd, J = 7.5, 1.0 Hz, 1H), 4.83 (s, 1H), 4.21 (s, 1H), 3.69–3.61 (m, 3H), 3.47 (dd, J = 12.3, 1.8 Hz, 1H), 3.10 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.5 Hz, 1H), 2.38 (td, J = 11.5, 2.7 Hz, 1H), 2.20 (qd, J = 12.3, 4.0 Hz, 1H), 1.87 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 155.7 (C), 145.1 (C), 142.4 (C), 137.6 (C), 129.6 (2CH), 129.5 (C), 128.4 (2CH), 127.4 (CH), 125.3 (C), 124.1 (CH), 122.5 (CH), 110.7 (CH₂), 108.2 (CH), 62.7 (CH₂), 60.8 (CH₂), 53.5 (CH₂), 41.9 (CH), 31.3 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₂₀H₂₀N₂O₂, 320.1525; found, 320.1523.

2-(1-Benzyl-3-methylenepiperidin-4-yl)-6-fluorophenol (13j)

Following the mw protocol, 13.4 mg of 13j (25%) was obtained as a yellow oil from 12j (53.0 mg, 0.18 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (10:1). R_f= 0.11 (hexanes/EtOAc = 6:1); ¹H NMR (500 MHz, CDCl₃): δ 7.37–7.32 (m, 4H), 7.28 (m, 1H), 6.97 (m, 2H), 6.82 (m, 1H), 4.82 (d, J = 2.0 Hz, 1H), 4.29 (d, J = 2.0 Hz, 1H), 3.65–3,60 (m, 3H), 3.47 (dd, J = 12.0, 1.5 Hz, 1H), 3.08 (m, 1H), 2.87 (dd, J = 12.8, 1.3 Hz, 1H), 2.33 (td, J = 12.0, 3.0 Hz, 1H), 2.11 (qd, J = 12.1, 4.1 Hz, 1H), 1.83 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 151.6 (d, J = 235.8 Hz, C), 146.0 (C), 142.0 (d, J = 13.6 Hz, C), 137.8 (C), 131.0 (C), 129.5 (2CH), 128.4 (2CH), 127.3 (CH), 124.5 (d, J = 3.1 Hz, CH), 120.0 (d, J = 7.3 Hz, CH), 113.6 (d, J = 18.3 Hz, CH), 110.1 (CH₂), 62.8 (CH₂), 60.8 (CH₂), 53.4 (CH₂), 41.6 (CH), 31.2 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₁₉H₂₁FNO, 298.1607; found, 298.1613.

3,5-Dimethoxy-2-(1-(4-methoxybenzyl)-3-methylenepiperidin-4-yl)phenol (13k)

Using the bath oil conditions, 0.37 g of 13k (65%) was obtained as a yellow oil from 12k (0.52 g, 1.53 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (6:1). R_f= 0.06 (hexanes/EtOAc = 3:1); ¹H NMR (500 MHz, CDCl₃): δ 7.27 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.12 (d, J = 2.5 Hz, 1H), 6.07 (d, J = 2.0 Hz, 1H), 4.88 (d, J = 2.0 Hz, 1H), 4.73 (d, J = 2.0 Hz, 1H), 4.10 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.75 (s, 3H), 3.60 (d, J = 12.5 Hz, 1H), 3.52 (m, 2H), 2.99 (m, 1H), 2.85 (d, J = 14.0 Hz, 1H), 2.25 (td, J = 11.0, 4.0 Hz, 1H), 2.06 (m, 1H), 1.78 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 159.9 (C), 159.1 (C), 158.7 (C), 156.5 (C), 144.9 (C), 130.7 (2CH), 129.2 (C), 113.9 (2CH), 110.5 (CH₂), 109.7 (C), 95.2 (CH), 91.5 (CH), 61.8 (CH₂), 59.3 (CH₂), 55.9 (CH₃), 55.4 (CH₃), 55.3 (CH₃), 52.1 (CH₂), 35.0 (CH), 29.3 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₂₂H₂₈NO₄, 370.2018; found, 370.2022.

3,5-Dimethoxy-2-(1-methyl-3-methylenepiperidin-4-yl)phenol (13l)

Following the bath oil conditions, 19.7 mg of 13l (50%) was obtained from 12l (40.0 mg, 0.15 mmol). The residue was purified by column chromatography with SiO₂ and eluted with EtOAc/MeOH (10:0.5) to give 13l as a white solid, mp = 109–202 °C.R_f= 0.08 (EtOAc/MeOH = 20:1); ¹H NMR (500 MHz, CDCl₃): δ6.10 (s, 1H), 6.06 (s, 1H), 4.91 (s, 1H), 4.64 (s, 1H), 4.0 (m, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.46 (d, J = 13.0 Hz, 1H), 3.01 (d, J = 10.0 Hz, 1H), 2.83 (d, J = 13.0 Hz, 1H), 2.39 (s, 3H), 2.27 (m, 2H), 1.72 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 159.9 (C), 158.8 (C), 156.6 (C), 143.1 (C), 110.8 (CH₂), 108.6 (C), 95.0 (CH), 91.2 (CH), 62.1 (CH₂), 55.9 (CH₃), 55.5 (CH₂), 55.3 (CH₃), 45.4 (CH₃), 35.0 (CH), 28.8 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₁₅H₂₁NO₃ 263.1521; found, 263.1516.

Synthetic Application; Flavonoid Alkaloids

2-Acetyl-6-(1–benzyl–3–methylenepiperidin–4-yl)-3,5-dimethoxyphenyl-2-chlorobenzoate (16)

To a solution of BF₃ etherate (5.32 mmol) in dry CH₂Cl₂ (5 mL) at 0 °C, under an argon atmosphere, distilled acetic anhydride (5.32 mmol) was added. The reaction mixture was stirred for 5 min, followed by the addition of a solution of 13e (0.38 mmol) in CH₂Cl₂ (6 mL). The resulting mixture was stirred at room temperature for 16 h, then quenched with a saturated aqueous solution of Na₂CO₃ until a yellow color appeared. The aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL). The organic layer was separated, dried with Na₂SO_4, and concentrated under reduced pressure. The crude reaction product was dissolved in 4 mL of a mixture of MeOH:H₂O (1:1), cooled in an ice bath and treated with KOH (powder, 0.95 mmol). After addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The MeOH was removed under reduced pressure and H₂O (3 mL) was added. The aqueous phase was extracted with CH₂Cl₂ (3 × 15 mL), and the organic layer was separated, treated with Na₂SO_4, and evaporated under reduced pressure to afford 14 as a yellow oil. Intermediate 14 (0.34 mmol), without purification, was dissolved in pyridine (3.5 mL) at 0 °C, and under argon atmosphere, 2-chlorobenzoyl chloride (1.02 mmol) was added dropwise. Once the addition was completed, the mixture was stirred at room temperature overnight. The reaction mixture was then treated with a saturated aqueous solution of Na₂CO_3. The aqueous phase was extracted with CH₂Cl₂ (3 × 5 mL) and washed with H₂O and brine. The organic layer was separated, dried with Na₂SO_4, and concentrated. The crude product was purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (3:1), yielding 0.13 g (65%) of 16 as a yellow oil. R_f = 0.31 (hexanes/EtOAc = 1:1); ¹H NMR (500 MHz, CDCl₃): δ 8.14 (d, J = 8.0 Hz, 1H), 7.46 (m, 2H), 7.38 (m, 1H), 7.29–7.20 (m, 5H), 6.45 (s, 1H), 4.70 (d, J = 3.0 Hz, 1H), 4.37 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.77 (m, 1H), 3.56 (d, J = 13.5 Hz, 1H), 3.47 (d, J = 13.0 Hz, 1H), 3.40 (d, J = 11.5 Hz, 1H), 2.97 (dd, J = 11.5, 3.5 Hz, 1H), 2.78 (d, J = 13.5 Hz, 1H), 2.54 (s, 3H), 2.45 (m, 1H), 2.21 (m, 1H), 1.62 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 200.6 (C), 163.8 (C), 160.8 (C), 157.6 (C), 147.4 (C), 143.4 (C), 138.6 (C), 134.0 (C), 132.9 (CH), 132.1 (CH), 130.9 (CH), 129.7 (C), 129.0 (2CH), 128.2 (2CH), 126.9 (CH), 126.9 (CH), 117.6 (C), 116.2 (C), 108.7 (CH₂), 93.5 (CH), 62.0 (CH₂), 60.9 (CH₂), 56.0 (CH₃), 56.0 (CH₃), 54.0 (CH₂), 38.9 (CH), 31.9 (CH₃), 29.3 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₃₀H₃₀ClNO₅, 519.1813; found, 519.1820.

8-(1-Benzyl-3-methylenepiperidin-4-yl)-2-(2-chlorophenyl)-5,7-dimethoxy-4H-chromen-4-one (17)

A solution of benzoate 16 (0.17 g, 0.38 mol) in pyridine (0.7 mL) with pulverized KOH (0.05 g, 0.95 mmol) was stirred at 55 °C for 1.5 h. The resulting black mixture was cooled with an ice bath, treated with a mixture of H₂O (3 mL) and HCl (concentrated, 0.50 mL), and allowed to react for 30 min. A saturated aqueous solution of Na₂CO₃ was added until the pH reached 9. The aqueous layer was extracted by CH₂Cl₂ (3 × 7 mL), and the combined organic layers were washed with H₂O and brine. The organic layer was dried with Na₂SO₄, and concentrated under reduced pressure, a yellow oil was obtained and used without further purification for the next step. The crude reaction was dissolved with a mixture of H₂SO₄ (0.05 mL) and glacial acetic acid (5.20 mL), and the reaction mixture was stirred at 100 °C for 1.5 h. Then, the reaction mixture was cooled to room temperature and a saturated solution of Na₂CO₃ was added until the pH reached 9. The aqueous layer was extracted with CH₂Cl₂ (3 × 7 mL), and the organic phase was dried with Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography with SiO₂ and eluted with EtOAc/Hex (2:1) to give 0.13 g (70%) of 17 as a yellow oil. R_f = 0.13 (EtOAc); ¹H NMR (500 MHz, CDCl₃): δ 7.76 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 7.8, 2.0 Hz, 1H), 7.44–7.38 (m, 2H), 7.34–7.23 (m, 5H), 6.63 (s, 1H), 6.48 (s, 1H), 4.74 (s, 1H), 4.26 (s, 1H), 4.11 (m, 1H), 4.03 (s, 3H), 3.95 (s, 3H), 3.59 (d, J = 13.5 Hz, 1H), 3.51 (d, J = 13.5 Hz, 1H), 3.47 (dd, J = 12.5, 2.0 Hz, 1H), 2.98 (m, 1H), 2.86 (dd, J = 12.0, 2.0 Hz, 1H), 2.55 (qd, J = 12.6, 4.0 Hz, 1H), 2.28 (td, J = 12.0, 2.5 Hz, 1H), 1.58 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 178.1 (C), 162.1 (C), 160.0 (C), 159.5 (C), 157.3 (C), 144.3 (C), 138.7 (C), 132.8 (C), 131.6 (C), 131.5 (CH), 131.2 (CH), 131.0 (CH), 129.1 (2CH), 128.2 (2CH), 127.2 (CH), 127.0 (CH), 113.9 (CH), 110.2 (C), 109.1 (C), 108.0 (CH₂), 92.2 (CH), 62.0 (CH₂), 61.0 (CH₂), 56.5 (CH₃), 56.0 (CH₃), 54.2 (CH₂), 38.3 (CH), 29.1 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₃₀H₂₉ClNO₄, 502.1785; found, 502.1776.

Synthetic Application; Chromone Alkaloids

8-(1-Benzyl-3-methylenepiperidin-4-yl)-5,7-dimethoxy-2-methyl-4H-chromen-4-one (19)

The intermediate 14 was prepared from 13e (0.11 g, 0.30 mmol) following the procedure described for the synthesis of 16. Without further purification, intermediate 14 was dissolved in dry EtOAc (5 mL) and sodium (80.0 mg, 3.48 mmol) was added. The reaction mixture was heated to reflux for 2 h, then, a saturated solution of Na₂CO₃ was added (2 mL) and the aqueous layer was extracted with EtOAc (3 × 10 mL). The organic phase was separated, dried with Na₂SO₄, and concentrated under reduced pressure. The residue was dissolved in EtOAc (2 mL) and concentrated HCl (0.01 mL) was added at room temperature. The reaction was stirred for 1 h and quenched with a solution of Na₂CO₃ until get pH = 9. The aqueous layer was extracted with EtOAc (3 × 10 mL), next, the organic phase was collected, dried, and concentrated. The residue was purified by column chromatography with SiO₂ and eluted with hexanes: EtOAc (1:1) to give 80.0 mg (67%) of 19 as a yellow oil. R_f = 0.10 (EtOAc); ¹H NMR (500 MHz, CDCl₃): δ 7.40–7.32 (m, 4H), 7.28 (m, 1H), 6.42 (s, 1H), 6.00 (s, 1H), 4.70 (s,1H), 4.17 (m, 1H), 4.03 (m, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 3.70 (d, J = 13.0 Hz, 1H), 3.62 (d, J = 13.0 Hz, 1H), 3.47 (dd, J = 12.5, 2.0 Hz, 1H), 3.06 (m, 1H), 2.91 (dd, J = 12.0, 1.5 Hz, 1H), 2.57 (qd, J = 12.5, 3.9 Hz, 1H), 2.37 (td, J = 12.0, 2.5 Hz, 1H), 2.30 (s, 3H), 1.60 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 178.3 (C), 163.1 (C), 161.5 (C), 159.8 (C), 157.3 (C), 143.9 (C), 138.4 (C), 129.2 (2CH), 128.3 (2CH), 127.1 (CH), 111.3 (CH), 109.7 (C), 108.8 (C), 107.8 (CH₂), 91.8 (CH), 61.9 (CH₂), 60.8 (CH₂), 56.3 (CH₃), 55.9 (CH₃), 54.1 (CH₂), 38.2 (CH), 29.2 (CH₂), 20.0 (CH₃). HRMS-EI m/z: [M]⁺ calcd for C₂₅H₂₇NO₄, 405.1940; found, 405.1940.

Synthesis of Chromone/Flavone Piperidine Alkaloids Containing Methyl Carbamate (Moc) Group

To a suspension of 17 or 19 (1.0 mmol) and NaHCO₃ (85.0 mg, 1.0 mmol) in dry toluene (20 mL) under N₂ atmosphere was added dropwise methyl chloroformate (0.1 mL, 1.2 mmol). Next, the reaction mixture was heated to reflux for 2 h. Then, the mixture of reaction was cooled, and the solids were filtered and washed with EtOAc (3 × 5 mL). The crude was concentrated for purification.

Methyl 4-(2-(2-Chlorophenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl)-3-methylenepiperidine-1-carboxylate (21)

Following the debenzylation protocol, 0.17 g of 21 (70%) was obtained as a colorless oil from 17 (0.26 g, 0.52 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (1:1). R_f = 0.22 (EtOAc); ¹H NMR (500 MHz, CD₃CN): δ 7.67 (d, J = 7.5 Hz, 1H), 7.55 (dd, J = 7.8, 1.3 Hz, 1H), 7.49 (td, J = 7.6, 1.8 Hz, 1H), 7.45–7.40 (m, 1H), 6.62 (s, 1H), 6.39 (br, 1H), 4.82 (s, 1H), 4.52 (m, 1H), 4.28 (s, 1H), 4.23 (m, 1H), 4.01 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.57 (m, 4H), 3.01 (br, 1H), 2.31 (qd, J = 13.0, 4.5 Hz, 1H), 1.60 (d, J = 11.0 Hz, 1H). ¹³C{¹H} NMR (125 MHz, CD₃CN): δ 177.4 (C), 162.9 (C), 160.9 (C), 160.0 (C), 157.9 (C), 156.2 (C), 144.2 (C), 133.0 (C), 132.8 (CH), 132.2 (C), 132.0 (CH), 131.6 (CH), 128.5 (CH), 114.4 (CH), 110.3 (C), 109.5 (C), 109.4 (CH₂), 93.8 (CH), 56.9 (CH₃), 56.8 (CH₃), 52.9 (CH₃), 51.2 (CH₂), 45.5 (CH₂), 38.3 (CH), 30.2 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₂₅H₂₅ClNO₆, 470.1370; found, 470.1345.

Methyl 4-(5,7-Dimethoxy-2-methyl-4-oxo-4H-chromen-8-yl)-3-methylenepiperidine-1-carboxylate (22)

Following the debenzylation protocol, 0.30 g of 22 (80%) was obtained as a white solid (mp = 155–157 °C) from 19 (0.41 g, 1.01 mmol). Purified with SiO₂ column chromatography and eluted with hexanes/EtOAc (1:2). R_f = 0.13 (EtOAc); ¹H NMR (500 MHz, CDCl₃): δ 6.41 (s, 1H), 5.99 (d, J = 0.5 Hz, 1H), 4.83 (m, 1H), 4.60 (m, 1H), 4.25 (br, 2H), 4.15 (m, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 3.74 (s, 3H), 3.70 (m, 1H), 3.08 (br, 1H), 2.40 (br, 1H), 2.22 (d, J = 1.0 Hz, 3H), 1.70 (d, J = 13.0 Hz, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 178.2 (C), 163.0 (C), 161.3 (C), 160.3 (C), 160.0 (C), 157.2 (C), 156.1 (C), 142.5 (C), 111.5 (CH), 109.6 (C), 108.9 (CH₂), 91.8 (CH), 56.5 (CH₃), 56.0 (CH₃), 52.7 (CH₃), 50.9 (CH₂), 45.1 (CH₂), 37.3 (CH), 29.5 (CH₂), 19.9 (CH₃). HRMS-EI m/z: [M]⁺ calcd for C₂₀H₂₃NO₆, 373.1525; found, 373.1520.

Installation of the cis-hydroxyl Group at C3′ Position (Oxidative Cleavage/Reduction)

A stream of ozone was bubbled through a solution of the corresponding alkene 21 or 22 (0.42 mmol) in MeOH (reagent grade, 10.0 mL) at −65 °C. Once raw material was consumed, N₂ was bubbled to the reaction, and S(CH₃)₂ (0.06 mL, 0.84 mmol) was added. The reaction mixture was stirred for 30 min at −35 °C and then, the solvent was removed at a reduced pressure. The residue (without purification) was solved in 10 mL of anhydrous THF. Next, L-selectride was dropwise added (0.5 mL of 1.0 M solution, 0.50 mmol) at −65 °C. The reaction mixture was stirred at the same temperature for 2 h. The reaction was quenched with a saturated solution of Rochelle salt (5.0 mL) and stirred at room temperature for 20 min. The aqueous layer was extracted with CH₂Cl₂ (4 × 10 mL) then the organic layer was separated, dried with Na₂SO_4, and concentrated for purification.

Methyl (3S,4R)-4-(2-(2-Chlorophenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl)-3-hydroxypiperidine-1-carboxylate (23)

Following the oxidative cleavage/reduction protocol, 0.14 g of 23 (68%) was obtained as a yellow oil from 21 (0.20 g, 0.42 mmol). Purified with SiO₂ column chromatography and eluted with EtOAc. R_f = 0.40 (EtOAc/MeOH = 10:1); ¹H NMR (500 MHz, CD₃CN): δ 7.81 (dd, J = 7.5, 2.0 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.50 (td, J = 7.5, 1.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 6.56 (s, 1H), 6.32 (s, 1H), 4.12 (m, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.86 (m, 1H), 3.62 (s, 3H), 3.57 (dt, J = 12.5, 2.7 Hz, 1H), 2.96 (br, 1H), 2.82 (m, 1H), 2.75 (br, 1H), 1.46 (d, J = 12.0 Hz, 1H). ¹³C{¹H} NMR (125 MHz, CD₃CN): δ 177.5 (C), 163.6 (C), 160.6 (C), 160.4 (C), 158.4 (C), 157.3 (C), 133.0 (C), 132.9 (CH), 132.5 (C), 132.2 (CH), 131.6 (CH), 128.5 (CH), 114.4 (CH), 111.4 (C), 109.6 (C), 94.1 (CH), 69.7 (CH), 57.1 (CH₃), 56.8 (CH₃), 52.9 (CH₃), 51.7 (CH₂), 46.1 (CH₂), 40.0 (CH), 24.9 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₂₄H₂₅ClNO₇ 474.1320; found, 474.1315.

Methyl (3S,4R)-4-(5,7-Dimethoxy-2-methyl-4-oxo-4H-chromen-8-yl)-3-hydroxypiperidine-1-carboxylate (24)

Following the oxidation protocol, 26.0 mg of 24 (50%) was obtained as a yellow oil from 22 (0.05 g, 0.14 mmol). Purified with SiO₂ column chromatography and eluted with EtOAc/MeOH (1.0:0.01). R_f = 0.23 (EtOAc/MeOH = 10:1); ¹H NMR (500 MHz, CDCl₃): δ 6.42 (s, 1H), 6.02 (s, 1H), 4.43 (br, 1H), 4.31 (br, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.94 (br, 1H), 3.75 (s, 3H), 3.60 (m, 1H), 3.02 (m, 1H), 2.87 (m, 2H), 2.31 (s, 3H), 1.53 (m, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 177.9 (C), 162.8 (C), 161.7 (C), 160.1 (C), 157.3 (C), 157.0 (C), 111.8 (CH), 109.8 (C), 109.2 (C), 92.2 (CH), 69.4 (CH), 56.5 (CH₃), 56.2 (CH₃), 52.9 (CH₃), 51.0 (CH₂), 45.6 (CH₂), 38.9 (CH), 24.0 (CH₂), 20.0 (CH₃). HRMS-FAB m/z: [M + H]⁺ calcd for C₁₉H₂₄NO₇ 378.1553; found, 378.1553.

Formal Synthesis of Rohitukine and Flavopiridol

Methyl 4-(2-Hydroxy-4,6-dimethoxyphenyl)-3-methylenepiperidine-1-carboxylate (25)

To a stirred solution of 13e (0.30 g, 0.88 mmol) and sodium bicarbonate (0.074 g, 0.88 mmol) in 18.0 mL of toluene anhydrous was added dropwise methyl chloroformate (0.17 mL, 2.20 mmol). The reaction mixture was heated to reflux and monitored by TLC until the total consumption of 13e. The resulting mixture was allowed to room temperature, filtered, and concentrated under reduced pressure. The product without purification was dissolved in a mixture of MeOH/H₂O (1:1, 9 mL), cooled to 0 °C, and treated with KOH (powder, 2.20 mmol), the reaction mixture was stirred for 1 h. The MeOH was removed, and the aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL), the organic phase was dried with Na₂SO₄ and concentrated. The residue was purified by column chromatography with SiO₂ and eluted with hexanes/EtOAc (3:1) to give 0.25 g (90%) of 25 as a colorless oil. R_f = 0.70 (EtOAc); ¹H NMR (500 MHz, CD₃CN): δ 6.89 (br, 1H), 6.12 (d, J = 2.0 Hz, 1H), 6.06 (d, J = 2.5 Hz, 1H), 4.77 (s, 1H), 4.51 (d, J = 14.0 Hz, 1H), 4.28 (s, 1H), 4.08 (br, 1H), 3.95 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.65 (s, 3H), 3.58 (m, 1H), 3.00 (br, 1H), 2.35 (qd, J = 12.9, 4.4 Hz, 1H), 1.53 (m, 1H). ¹³C{¹H} NMR (125 MHz, CD₃CN): δ 160.7 (C), 160.6 (C), 157.2 (C), 156.6 (C), 144.9 (C), 109.7 (C), 109.1 (CH₂), 95.0 (CH), 92.0 (CH), 56.2 (CH₃), 55.8 (CH₃), 53.0 (CH₃), 51.3 (CH₂), 45.7 (CH₂), 38.2 (CH), 30.3 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₁₆H₂₂NO₅ 308.1498; found, 308.1508.

Methyl (3S,4R)-3-Hydroxy-4-(2,4,6-trimethoxyphenyl)piperidine-1-carboxylate (27)

A solution of 25 (0.25 g, 0.81 mmol) in 8 mL of THF anhydrous was added to a flask with NaH (0.58 g, 2.43 mmol) under N₂ atmosphere at 0 °C temperature. After 10 min 0.06 mL of CH₃I (0.89 mmol) was added, and the reaction was carried to room temperature. The reaction mixture was stirred for 1h, quenched with H₂O (2 mL), and extracted with CH₂Cl₂ (4 × 10 mL). The organic phase was dried with Na₂SO₄ and concentrated for the next step. Then, a stream of ozone was bubbled through a solution of alkene (without purification) 26 in MeOH (8.0 mL) at −65 °C for 1.5 h followed by bubbled N₂ to the reaction and addition of S(CH₃)₂ (0.12 mL, 1.62 mmol). The reaction mixture was stirred for 30 min at −35 °C. The solvent was removed at reduced pressure, and the residue was solved in 10 mL of THF anhydrous. Then, a 1.0 M solution of L-selectride was dropwise added (0.98 mL, 0.97 mmol) at −65 °C. After 2 h, the reaction was quenched with a saturated solution of Rochelle salt (5.0 mL) and stirred to room temperature for 20 min. The aqueous layer was extracted with CH₂Cl₂ (4 × 10 mL) and the organic layer was separated, dried with Na₂SO_4, and concentrated. The crude product was purified by column chromatography with SiO₂ and eluted with hexanes/EtOAc (2:1) to give 0.15 g (59%) of 27 as a white solid, mp = 86–89 °C. R_f = 0.53 (EtOAc);¹H NMR (500 MHz, CDCl₃): δ 6.17 (s, 2H), 4.38 (br, 1H), 4.20 (br, 1H), 3.84 (br, 1H), 3.81 (s, 9H), 3.73 (s, 3H), 3.54 (m, 1H), 2.97 (m, 1H), 2.83 (br, 1H), 2.74 (qd, J = 13.0, 4.0 Hz, 1H), 1.36 (d, J = 13.5 Hz, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 160.1 (C), 159.1 (2C), 157.2 (C), 111.3 (C), 91.6 (2CH), 69.9 (CH), 56.0 (2CH₃), 55.5 (CH₃), 52.7 (CH₃), 50.9 (CH₂), 45.5 (CH₂), 37.8 (CH), 24.0 (CH₂). HRMS-EI m/z: [M]⁺ calcd for C₁₆H₂₃NO₆, 325.1525; found, 325.1523.

(3S,4R)-1-Methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol (28)

A solution of 27 (65.0 mg, 0.2 mmol) in THF anhydrous (4.0 mL) was added to a flask with LiAlH₄ (22.0 mg, 0.6 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 2 h. Then, 2.0 mL of H₂O was added, and the aqueous phase was extracted with CH₂Cl₂ (4 × 10 mL). The organic layer was separated, dried with Na₂SO₄, and concentrated. The crude product was purified by column chromatography with SiO₂ and eluted with a gradient system MeOH/EtOAc (0.1:1) to MeOH to give 31.0 mg (65%) of 28 as a colorless oil. The NMR data agree with those reported by Naik.^8aR_f = 0.10 (EtOAc/MeOH = 10:1); ¹H NMR (500 MHz, CDCl₃): δ 6.16 (s, 2H), 3.84 (br, 1H), 3.80 (s, 9H), 3.37 (dt, J = 13.5, 3.3 Hz, 1H), 2.99 (m, 2H), 2.89 (qd, J = 13.0, 3.9 Hz, 1H), 2.31 (s, 3H), 2.14 (d, J = 12.5 Hz, 1H), 2.04 (td, J = 11.9, 2.8 Hz, 1H), 1.40 (dd, J = 13.5, 3.5 Hz, 1H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 159.8 (C), 159.3 (2C), 111.7 (C), 91.6 (2CH), 70.6 (CH), 62.7 (CH₂), 57.2 (CH₂), 55.9 (2CH₃), 55.4 (CH₃), 46.7 (CH₃), 37.2 (CH), 24.7 (CH₂). HRMS-FAB m/z: [M + H]⁺ calcd for C₁₅H₂₄NO₄, 282.1705; found, 282.1711.

Data Availability Statement

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

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c01926.

• ¹H and ¹³C{¹H} spectra for new compounds (PDF)

The authors declare no competing financial interest.