Syntheses of Highly Substituted Furan and Pyrrole Derivatives via Lithiated 3-Aryl-1-methoxyallenes: Application to the Synthesis of Codonopsinine

Abstract

Lithiated 1-methoxy-3-phenylallenes were generated in situ from a phenyl-substituted propargylic ether. They smoothly combined with aldehydes, ketones, or imines to give allenyl adducts, which cyclized to highly substituted heterocycles either under basic conditions or with silver nitrate assistance. Analogously, a dihydropyrrole derivative was obtained by the addition of ­anisyl-substituted lithiated methoxyallene derivative to an N-tosyl imine and subsequent cyclization of the intermediate. The two diaste­reomers obtained were subsequently transformed into the alkaloid (±)-codonopsinine and one of its epimers. The key steps of these ­sequences are highly diastereoselective hydroborations of silyl enol ethers quantitatively leading to hydroxylated intermediates.

methoxyallene - organo lithium compounds - pyrroles - hydroboration - alkaloids

References and Notes

Reviews:

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1b Zimmer R. Synthesis  1993,  165 

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2 Hoff S. Brandsma L. Arens JF. Recl. Trav. Chim. Pays-Bas  1968,  87:  916 

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Selected references:

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6 For early attempts to generate this type of allene, see: Leroux Y. Mantione R. J. Organomet. Chem.  1971,  30:  295 

For selected recent syntheses of 2,5-disubstituted dihydropyrroles:

7a Jones AD. Knight DW. Redfern AL. Gilmore J. Tetrahedron Lett.  1999,  40:  3267 

7b Evans PA. Robinson JE. Org. Lett.  1999,  1:  1929 

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7j Ohno H. Kadoh Y. Fujii N. Tanaka T. Org. Lett.  2006,  8:  947 

For selected recent syntheses of 2,5-disubstituted dihydrofurans:

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10 Compounds such as 1 are easily prepared by Sonogashira reactions of the corresponding propargylic ethers: Roesch SKR. Larock RC. J. Org. Chem.  2001,  66:  412 

11

Conversion of 9 into 13; Typical Procedure To a solution of 1-methoxy-4-(3-methoxy-1-propynyl)ben-zene (9; 1.20 g, 6.82 mmol) in Et₂O (15 mL) n-BuLi (2.5 M in hexane, 2.73 mL, 6.82 mmol) was added at -78 °C and stirred for 1 h. MeOH (276 µL, 6.82 mmol) was added slowly to the mixture and the resulting solution was warmed with stirring to r.t. (0.5 h). The mixture was cooled again to -78 °C and n-BuLi (2.73 mL, 6.82 mmol) was added slowly and the resulting solution was stirred for 0.5 h. Imine 11 (1.34 g, 6.82 mmol) dissolved in Et₂O (15 mL) was slowly transferred to the reaction flask by syringe. After stirring for 1.5 h at -78 °C to -20 °C, the mixture was quenched with H₂O and the aqueous phase was extracted with Et₂O (3 × 25 mL). The combined organic phases were washed with brine (25 mL) and dried with MgSO₄. Filtration and evaporation of solvents in vacuo at r.t. afforded allenyl amine 12 (3.17 g, dr ca. 50:50), which was used for the subsequent cyclization without purification. The crude product was dissolved in anhyd MeCN (45 mL); K₂CO₃ (2.35 g, 17.0 mmol) followed by AgNO₃ (289 mg, 1.70 mmol) were added to the solution. The resulting mixture was stirred for 16 h in the dark under argon, then filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo at r.t. The resulting product was purified by column chromatography on silica gel (hexane-EtOAc, 4:1) to give 13 (1.98 g, 78% from 9) as a mixture of diastereomers (trans/cis 45:55). Isomers (2,5-trans)-13 (650 mg, 25%) and (2,5-cis)-13 (1.12 g, 44%) were separated by fractional crystallization.
3-Methoxy-5-(4-methoxyphenyl)-2-methyl-1-tosyl-2,5-dihydro-1 H -pyrrole (2,5- trans )-13. Colorless crystals; mp 138-140 °C. IR (KBr): 3100-3000 (=CH), 3000-2840 (CH), 1670 (C=C), 1610 (CN), 1340, 1160 (RSO₂N) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.63 (d, J = 6.3 Hz, 3 H, Me), 2.31 (s, 3 H, Ts-Me), 3.62, 3.77 (2 s, 3 H each, OMe), 4.40-4.52 (m, 2 H, 2-H, 5-H), 5.50 (dd, J = 1.9, 4.7 Hz, 1 H, 4-H), 6.55-6.65, 6.90-7.00, 7.00-7.10 (3 m, 2 H, 4 H, 2 H, Ar). ¹³C NMR (126 MHz): δ = 20.9, 21.4 (2 q, Me), 55.4, 57.1 (2 q, OMe), 60.2 (d, C-2), 67.5 (d, C-5), 94.6 (d, C-4), 113.3, 126.7, 128.8, 129.9 (4 d, Ar), 132.1, 138.4, 141.9, 159.4 (4 s, Ar), 157.8 (s, C-3). MS (EI, 80 eV, 30 °C):
m/z (%) = 373 (30) [M]⁺, 358 (13) [M - CH₃]⁺, 266 (26) [M - C₇H₇O]⁺, 218 (100) [M - C₇H₇SO₂]⁺, 155 (40) [C₇H₇SO₂]⁺. HRMS (EI, 80 eV, 30 °C): m/z calcd for C₂₀H₂₃NO₄S: 373.13478; found: 373.13450. Anal. Calcd for C₂₀H₂₃NO₄S (373.5): C, 64.32; H, 6.21; N, 3.75. Found: C, 64.29; H, 6.32; N, 3.69.
(2,5- cis )-13. Brownish liquid. IR (KBr): 3100-3000 (=CH), 3000-2840 (CH), 1665 (C=C), 1610 (CN), 1350, 1160 (RSO₂N) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.50 (d, J = 6.3 Hz, 3 H, Me), 2.39 (s, 3 H, Ts-Me), 3.54, 3.78 (2 s, 3 H each, OMe), 4.30-4.42 (m, 2 H, 2-H, 5-H), 5.35 (m, 1 H, 4-H), 6.80-6.90, 7.20-7.35, 7.60-7.65 (3 m, 2 H, 4 H, 2 H, Ar). ¹³C NMR (126 MHz): δ = 21.6, 21.8 (2 q, Me), 55.4, 57.3 (2 q, OMe), 60.3 (d, C-2), 67.2 (d, C-5), 94.0 (d, C-4), 113.8, 127.7, 128.4, 129.6 (4 d, each, Ar), 134.9, 135.5, 143.4, 159.2 (4 s, Ar), 157.3 (s, C-3). MS (EI, 80 eV, 30 °C): m/z (%) = 373 (8) [M]⁺, 358 (2) [M - CH₃]⁺, 266 (11) [M - C₇H₇O]⁺, 218 (48) [M - C₇H₇SO₂]⁺, 217 (100), 155 (9) [C₇H₇SO₂]⁺. HRMS (EI, 80 eV, 30 °C): m/z calcd for C₂₀H₂₃NO₄S: 373.13478; found: 373.13432.

12a Olsson L.-I. Claesson A. Synthesis  1979,  743 

12b Marshall JA. Bartley GS. J. Org. Chem.  1994,  59:  7169 

12c Flögel O. Reissig H.-U. Eur. J. Org. Chem.  2004,  2797 

Isolation and structural determination:

13a Matkhalikova SF. Malikov VM. Yunusov SY. Khim. Prir. Soedin.  1969,  5:  606 

13b Matkhalikova SF. Malikov VM. Yunusov SY. Khim. Prir. Soedin.  1969,  5:  30 

Previous syntheses of this compound:

13c Iida H. Yamazaki N. Kibayashi C. J. Org. Chem.  1987,  52:  1956 

13d Severino EA. Correia CRD. Org. Lett.  2000,  2:  3039 

13e Goti A. Cicchi S. Mannucci V. Cardona F. Guarna F. Merino P. Tejero T. Org. Lett.  2003,  5:  4235 

13f Toyao A. Tamura O. Takagi H. Ishibashi H. Synlett  2003,  35 

13g Haddad M. Larchevêque M. Synlett  2003,  274 

13h Chandrasekhar S. Jagadeshwar V. Prakash SJ. Tetrahedron Lett.  2005,  46:  3127 

14 Heathcock CH. Blumenkopf TA. Smith KM. J. Org. Chem.  1989,  54:  1548