Efficient Synthesis of 5-Functionalised 2-Methoxypyridines and their Transformation to Bicyclic δ-Lactams, both Accessed Using Magnesium ‘Ate’ Complexes as Key Reagents

Abstract

Simple and efficient synthesis of 5-functionalised ­2-methoxypyridines from 5-bromo-2-methoxypyridine using ­[n-Bu₃Mg]Li performed in noncryogenic conditions is described. Application of 5-functionalised 2-methoxypyridines in the synthesis of 1-substituted 3,6,9,9a-tetrahydroquinolizin-4-ones and 3,5,8,8a-tetrahydro-1H-quinolin-2-ones via allylation of the corresponding 5-functionalised N-allyl(or benzyl)pyridin-2-ones using ­[allyln-Bu₂Mg]Li followed by ring-closing metathesis is presented.

Key words

magnesium ‘ate’ complexes - magnesiates - bromine-magnesium exchange - allylation - quinolizidin-4-ones - RCM

References and Notes

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13

Typical Procedure of 5-Functionalisation of 2-Methoxy-pyridine
To a cooled (0 ˚C) and stirred solution of n-BuMgCl (4.2 mmol, 2.1 mL, 2.0 M in THF) in dry THF (4 mL) in a Schlenk flask, n-BuLi (8.4 mmol, 3.4 mL, 2.5 M in hexane) was added via syringe over 1 min under argon, and the mixture was stirred for 5 min. To a yellow, cooled (-2 to 0 ˚C) solution 5-bromo-2-methoxypyridine (8.4 mmol, 1.09 mL) was added via syringe. The resulting solution was stirred for 30 min at -2 to 0 ˚C, then the electrophile was added (Table  [¹] ), and the mixture was continuously stirred for 30 min at 0 ˚C and 1 h at r.t. After addition of aq sat. NH₄Cl (5 mL), the aqueous layer was extracted with EtOAc (2 × 75 mL), and the combined organic layers were dried over MgSO₄. Filtration, concentration in vacuo, and purification by distillation or flash column chromatography yielded compound 3.

14

Typical Procedure of Transformation of 3 to Bicyclic Lactams 7
The mixture of 3 (5.5 mmol), NaI (11 mmol), and allyl bromide (38.5 mmol) was heated in MeCN (30 mL) at 55 ˚C for 1-6 d (see Table  [²] ). Subsequently, the solvent was evaporated and brine containing 1% Na₂S₂O₃ was added. The aqueous solution was extracted with EtOAc (2 × 75 mL), and the combined organic layers were dried over MgSO₄. Filtration, concentration in vacuo, and purification by flash column chromatography yielded 4. To a cooled (0 ˚C) and stirred solution of allylMgCl (4.9 mmol, 2.45 mL, 2.0 M in THF) in dry THF (4 mL) in a Schlenk flask n-BuLi (9.8 mmol, 3.9 mL, 2.5 M in hexane) was added via syringe under argon, the mixture was stirred for 5 min and then cooled to -72 ˚C. The mixture containing 1b was next transferred via syringe to a cooled (-72 ˚C) solution of N-allylpyridin-2-one (4, 9.0 mmol) in THF (20 mL). The resulting solution was stirred for 20 min at -72 ˚C, and then aq sat. NH₄Cl (10 mL) was added. The aqueous layer was extracted with EtOAc (2 × 75 mL), and the combined organic layers were dried over MgSO₄. Filtration, concentration in vacuo, and separation by flash column chromatography yielded 5. To a solution of 1,6-diallyl lactam 5 (1.0 mmol) in dry, degassed toluene (10 mL), ruthenium catalyst 8 or 9 was added, and the reaction mixture was stirred under slowly bubbled stream of argon at 70 ˚C. After the reaction was complete (Table  [²] ), the solvent was evaporated at reduced pressure, and the residue was left standing for 48 h followed by purification on column chromatography.

15

Selected Spectroscopic Data
2-Methoxy-5-trimethylsilanylpyridine (3b) Colorless oil. IR (film): 2956, 1586, 1556, 1488, 1352, 1286, 1250, 1116, 1026, 840 cm^-¹. MS (EI, 70 eV): m/z (%) = 181 (32) [M⁺], 180 (17), 166 (100), 136 (7). ^¹H NMR (400.1 MHz, CDCl₃): δ = 0.26 (9 H, s, Me₃Si), 3.94 (3 H, s, OCH₃), 6.74 (1 H, dd, J = 8.3, 0.8 Hz, =CH-3), 7.65 (1 H, dd, J = 8.3, 1.9 Hz, =CH-4), 8.24 (1 H, dd, J = 1.8, 0.8 Hz, =CH-6). ^¹³C NMR (100.6 MHz, CDCl₃): δ = -1.1 (Me₃Si), 53.3 (OCH₃), 110.6 (CH-3), 126.3 (C-5), 143.5 (CH-4), 151.6 (CH-6), 164.8 (C-2). HRMS (EI): m/z calcd for C₉H₁₅NOSi: 181.0923; found: 181.0922.
1-Trimethylsilanyl-3,6,9,9a-tetrahydroquinolizin-4-one (7b) Colorless oil. IR (film): 3036, 2960, 1666, 1644, 1468, 1444, 1404, 1296, 1254, 1116, 840, 760 cm^-¹. MS (EI, 70 eV): m/z (%) = 221 (79) [M⁺], 220 (100), 206 (12), 152 (14), 148 (23), 124 (23), 100 (34), 73 (28). ^¹H NMR (400.1 MHz, CDCl₃): δ = 0.15 (9 H, s, Me₃Si), 2.00-2.10 (1 H, m, CHH-9), 2.34 (1 H, dm, J = ca. 17.1 Hz, CHH-9), 2.97-3.01 (2 H, m, CH₂-3), 3.42 (1 H, dm, J = ca. 18.3 Hz, CHH-6), 4.16 (1 H, dq, J = 11.5, 3.4 Hz, CH-9a), 5.06 (1 H, dm, J = 18.3 Hz, CHH-6), 5.69-5.76 (1 H, m, =CH-7), 5.76-5.83 (1 H, m, =CH-8), 6.02 (1 H, ddd, J = 4.2, 3.2, 1.0 Hz, =CH-2). ^¹³C NMR (100.6 MHz, CDCl₃): δ = -1.1 (Me₃Si), 32.9 (CH₂-3), 34.1 (CH₂-9), 41.7 (CH₂-6), 57.6 (CH-9a), 124.8 (=CH-8), 125.0 (=CH-7), 131.1 (=CH-2), 137.21 (C-1), 166.1 (C-4). HRMS (EI): m/z calcd for C₁₂H₁₉NOSi: 221.1236; found: 221.1234.