Lactam Enolate-Pyridone
Addition: Synthesis of 4-Halocytisines

Patrick Durkin; Pietro Magrone; Stella Matthews; Clelia Dallanoce; Timothy Gallagher

doi:10.1055/s-0030-1259006

LETTER

Lactam Enolate-Pyridone Addition: Synthesis of 4-Halocytisines

Patrick Durkin^a, Pietro Magrone^a,b, Stella Matthews^a, Clelia Dallanoce^b, Timothy Gallagher*^a
^a School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK
Fax: +44(117)9251295; e-Mail: t.gallagher@bristol.ac.uk;
^b Università degli studi di Milano, Dipartimento di Scienze Farmaceutiche ‘Pietro Pratesi’, via L. Mangiagalli, 20133 Milan, Italy

Abstract

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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.

Key words

cytisine - 4-halocytisine - cyfusine

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References

References and Notes

Synthetic chemistry:

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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)

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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]⁺.

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]⁺.

<A NAME="RD25510ST-13">13</A> Stanetty P. Turner M. Mihovilovic MD. Molecules 2005, 10: 367 ; and ref. 4d

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

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