Lactam Enolate-Pyridone Addition: Synthesis of 4-Halocytisines

Abstract

The application of a lactam enolate-pyridone addition sequence, originally developed for cytisine, has been applied successfully to generate the first examples of 4-halocytisines. Variation of the lactam component provides cyfusine and 4-fluorocyfusine.

cytisine - 4-halocytisine - cyfusine

References and Notes

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2 Etter JF. Arch. Intern. Med.  2006,  166:  1553 

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3b Coe JW. Vetelino MG. Bashore CG. Wirtz MC. Brooks PR. Arnold EP. Lebel LA. Fox CB. Sands SB. Davis TI. Schulz DW. Rollema H. Tingley FD. O’Neill BT. Bioorg. Med. Chem. Lett.  2005,  15:  2974 

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8 Leznoff CC. Svirskaya PI. Yedidia V. Miller JM.
J. Heterocycl. Chem.  1985,  22:  145 

9

The synthesis of 4-fluoropyridone 4, [8] which involves separation of a mixture of 4- and 5-nitropyridines, proved problematic in terms of extraction/isolation of the intermediate 4-amino-2-methoxypyridine. Consequently,
an alternative procedure [¹0] based on commercially available 4-amino-2-chloropyridine was employed. While this still suffers from issues of volatility associated with I, this intermediate was not isolated but was carried through directly to pyridone 4 (Scheme  [5] )

Scheme 5 Synthesis of 4-fluoropyridone (4)

10a Urban R. Schnider O. Helv. Chim. Acta  1964,  47:  363 

10b Morgentin R. Pasquet G. Boutron P. Jung F. Lamorlette M. Maudet M. Ple P. Tetrahedron  2008,  64:  2772 

11

All novel compounds described were prepared as racemates and have been characterized fully. Data for key final compounds are presented.
Data for 4-Fluorocytisine (8) ^¹H NMR (400 MHz, CDCl₃): δ = 1.96 (2 H, t, J = 3.0 Hz, H8), 2.31-2.37 (1 H, m, H9), 2.87-2.92 (1 H, m, H7), 2.96-3.14 (4 H, m, H11, H13), 3.87 (1 H, ddt, J = 15.5, 6.5, 1.0, 1.0 Hz, H10), 4.08 (1 H, d, J = 15.5 Hz, H10), 5.89 (1 H, dd, J = 7.0, 3.0 Hz, H5), 6.10 (1 H, dd, J = 11.0, 3.0 Hz, H3), no resonance attributed to NH was observed. ^¹³C NMR (100 MHz, CDCl₃): δ = 26.2 (CH₂, C8), 27.6 (CH, C9), 36.0 (d, J = 2.5 Hz, CH, C7), 49.8 (CH₂, C10), 52.9 (CH₂, C11), 53.7 (CH₂, C13), 96.5 (d, J = 26.0 Hz, CH, C5), 99.7 (d, J = 16.5 Hz, CH, C3), 153.5 (d, J = 13.5 Hz, C, C6), 164.9 (d, J = 19.0 Hz, C=O, C2), 169.9 (d, J = 264.0 Hz, CF, C4). ^¹9F NMR (376 MHz, CDCl₃): δ = -99.9 (m). HRMS: m/z calcd for C₁₁H₁₄FN₂O: 209.1090; found: 209.1095 [M + H]⁺.

12

Data for 4-Bromocytisine (12)
^¹H NMR (400 MHz, CDCl₃): δ = 1.55 (1 H, br s, NH), 1.96 (2 H, m, H8), 2.35 (1 H, m, H9), 2.89 (1 H, m, H7), 2.98-3.12 (4 H, m, H11, H13), 3.86 (1 H, ddd, J = 15.5, 6.5, 1.0 Hz, H10), 4.06 (1 H, d, J = 15.5 Hz, H10), 6.20 (1 H, d, J = 2.0 Hz, H5), 6.70 (1 H, d, J = 2.5 Hz, H3). ^¹³C NMR (100 MHz, CDCl₃): δ = 26.3 (CH₂, C8), 27.7 (CH, C9), 35.6 (CH, C7), 49.9 (CH₂, C10), 53.1, 53.8 (CH₂, C11, C13), 109.0 (CH, C5), 118.9 (CH, C3), 135.1 (C, C4), 151.6 (C, C6), 162.6 (C=O, C2). HRMS: m/z calcd for C₁₁H₁₃ ⁷⁹BrN₂O: 268.0211; found: 268.0216 [M]⁺.

Data for 4-Chlorocytisine (13)
^¹H NMR (400 MHz, CDCl₃): d = 1.55 (1 H, br s, NH), 1.96 (2 H, m, H8), 2.35 (1 H, m, H9), 2.89 (1 H, m, H7), 2.98-3.12 (4 H, m, H11, H13), 3.87 (1 H, ddd, J = 15.6, 6.6, 1.2 Hz, H10), 4.08 (1 H, d, J = 15.6 Hz, H10), 6.07 (1 H, d, J = 2.0 Hz, H5), 6.50 (1 H, d, J = 2.2 Hz, H3). ^¹³C NMR (100 MHz, CDCl₃): d = 26.3 (CH₂, C8), 27.7 (CH, C9), 35.7 (CH, C7), 49.9 (CH₂, C10), 53.5, 54.2 (CH₂, C11, C13), 106.5 (CH, C5), 115.4 (CH, C3), 146.0 (C, C4), 151.6 (C, C6), 162.6 (C=O, C2). HRMS: m/z calcd for C₁₁H₁₄ ^³5ClN₂O: 225.0795; found: 225.0784 [M + H]⁺.

13 Stanetty P. Turner M. Mihovilovic MD. Molecules  2005,  10:  367 ; and ref. 4d

14

Data for Cyfusine (17)
^¹H NMR (400 MHz, CDCl₃): δ = 2.94 (1 H, dd, J = 11.0, 3.0 Hz, H6), 3.03-3.20 (3 H, m, H6, H8, H8a), 3.24 (1 H, dd, J = 11.5, 7.5 Hz, H8), 3.87 (1 H, td, J = 8.0, 2.5 Hz, H5b), 4.00 (1 H, dd, J = 13.5, 3.5 Hz, H9), 4.33 (1 H, dd, J = 13.5, 9.0 Hz, H9), 6.10 (1 H, dt, J = 7.0, 1.0 Hz, H5), 6.41 (1 H, dt, J = 9.0, 1.0 Hz, H3), 7.37 (1 H, dd, J = 9.0, 7.0 Hz, H4), no resonance attributed to NH was observed. ^¹³C NMR (100 MHz, CDCl₃): δ = 38.5 (CH, C8a), 50.9 (CH, C5b), 54.7 (CH₂, C8), 54.9 (CH₂, C6), 55.1 (CH₂, C9), 101.0 (CH, C5), 117.3 (CH, C3), 140.6 (CH, C4), 153.7 (C, C5a), 162.1 (C=O, C2). HRMS: m/z calcd for C₁₀H₁₃N₂O: 177.1028; found: 177.1023 [M + H]⁺. This compound has been reported previously,⁵ however, no analytical data were provided and these have been included here for comparison with 19.^¹5

15

The following numbering system was applied for 8-fluoro-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-a]indolizin-6 (9bH)-one (19, Figure  [²] ), in order to parallel that for cytisine.
Data for 4-Fluorocyfusine (19)
^¹H NMR (500 MHz, CDCl₃): δ = 2.95 (1 H, dd, J = 11.0, 3.0 Hz, H6), 3.07-3.21 (3 H, m, H6, H8, H8a), 3.25 (1 H, dd, J = 11.5, 7.5 Hz, H8), 3.85 (1 H, td, J = 8.0, 2.0 Hz, H5b), 3.96 (1 H, dd, J = 13.5, 3.5 Hz, H9), 4.30 (1 H, dd, J = 13.5, 8.5 Hz, H9), 5.97 (1 H, ddd, J = 6.5, 2.5, 1.0 Hz, H5), 6.05 (1 H, ddd, J = 11.0, 2.5, 1.0 Hz, H3), no resonance attributed to NH was observed. ^¹³C NMR (125 MHz, CDCl₃): δ = 38.6 (CH, C8a), 50.7 (CH, C5b), 54.4 (CH₂, C8), 54.7 (CH₂, C6), 54.9 (CH₂, C9), 93.1 (d, J = 28.0 Hz, CH, C3), 100.5 (d, J = 17.5 Hz, CH, C5), 155.8 (d, J = 13.5 Hz, C, C5a), 162.5 (d, J = 18.5 Hz, C=O, C2), 171.9 (d, J = 265.0 Hz, CF, C4). ^¹9F NMR (376 MHz, CDCl₃): δ = -97.14 (m). HRMS: m/z calcd for C₁₀H₁₂FN₂O: 195.0928; found: 195.0930 [M + H]⁺.

Figure 2