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Synlett 2010(18): 2789-2791  
DOI: 10.1055/s-0030-1259006
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Lactam Enolate-Pyridone Addition: Synthesis of 4-Halocytisines

Patrick Durkina, Pietro Magronea,b, Stella Matthewsa, Clelia Dallanoceb, 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

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Publication History

Received 14 September 2010
Publication Date:
14 October 2010 (online)

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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

Cytisine (1, Figure  [¹] ) has attracted much interest as a potent, high-affinity ligand for neuronal acetylcholine receptors, behaving as a partial agonist at α4β2 and a full agonist at α7. [¹] In this sense, cytisine is linked to nicotine addiction and has not only served as a smoking cessation aid in its own right (within Eastern Europe [²] ) but also as the drug discovery lead for varenicline (2), which was launched by Pfizer in 2006. [³]

Figure 1

We have described an efficient and highly convergent synthetic approach to cytisine and other lupin alkaloids where the key step is the intramolecular 1,6-addition of a lactam enolate to a pendant 2-pyridone (Scheme  [¹] ). [4]

Scheme 1 Lactam enolate addition approach to cytisine (1)

Mechanistic studies relating to this process have been reported recently [4d] and herein we describe an ability to vary the pyridone component together with the lactam moiety to provide a series of novel 4-halogenated pyridone variants of cytisine. This includes the application of the lactam enolate/pyridone addition strategy to provide a new entry to cyfusine, a ‘deconstructed’ cytisine variant originally reported by Yohannes and co-workers. [5]

A full range of halocytisines has been profiled as nicotinic ligands, but only the 3- or 5-monohalo, and 3,5-dihalo variants have been reported, [6] these being prepared from cytisine by halogenation of the pyridone moiety. 4-Substituted cytisines are not accessible from cytisine itself [7] and halogenated variants at this site therefore present a challenge and a gap in terms of structure-activity determination.

The synthesis of 4-fluorocytisine (8) is shown in Scheme  [²] and is based on use of 4-fluoropyridone (4) [8] [9] as the Michael acceptor. N-Alkylation of 4 with bromide 3 provided lactam 5 in 73% yield; competing O-alkylation was observed but was invariably of the order of 10% and this byproduct could be readily separated by chromatography. Exposure of 5 to LiHMDS promoted enolization and intramolecular 1,6-addition to give a 2.3:1 mixture of α- and β-adducts α-6 and β-6; only α-6 is shown and these assignments were based on NOE experiments. As in earlier studies, [4d] subsequent oxidation of 6 was dependent on the configuration at C(6), with the α-adduct α-6 undergoing MnO2-mediated oxidation (much more rapidly than diastereomer β-6) to re-establish the pyridone oxidation level. Selective lactam reduction of 7 followed by N-­debenzylation gave 4-fluoropyridone 8 [¹¹] in 21% overall yield from 3 (based on conversion of α-6 only).

Scheme 2 Synthesis of 4-fluorocytisine (8)

Extending this chemistry to 4-bromocytisine (12) then required simple variation of the pyridone component (Scheme  [³] ). A similar sequence to that outlined in Scheme  [²] , based on 4-bromopyridone (9), provided tricycle 10 after MnO2 oxidation. However, the lability of the 4-bromo substituent meant that an alternative deprotection sequence was necessary. Borane reduction of 10 proceeded smoothly and subsequent debenzylation of piperidine 11 was achieved using 1-chloroethyl chloroformate, followed by methanolysis. Interestingly, this sequence provided two separable products, 4-bromocytisine (12) and the corresponding 4-chlorocytisine (13) in a 3:1 ratio and in 69% overall yield. [¹²]

Scheme 3 Synthesis of 4-bromocytisine (12) and 4-chlorocytisine (13)

The halide exchange (11 → 12 and 13) presumably arises during the initial N-acylation-debenzylation step as the halide residues both survive methanolysis.

Cyfusine (17) [5] represents an example of a ‘deconstructed’ cytisine and we now report a new approach to both cyfusine and 4-fluorocyfusine (19) based on lactam enolate-pyridone addition (Scheme  [4] ). The requisite pyrrolidinone precursor 14 has been reported previously [¹³] [4d] and cyclization of lactam 15 proceeded in quantitative yield to give 16 as a 1:3 mixture of α- and β-isomers; only the major component (β-16) is shown. In this case, and presumably because 16 is conformationally less rigid than the piperidinone variants (e.g., 6), both the α- and β-16 underwent smooth oxidation. Lactam reduction and conventional N-debenzylation then completed the synthesis of cyfusine (17). [¹4] Variation of both the lactam and pyridone units is also illustrated in Scheme  [4] providing 4-fluorocyfusine (19) [¹5] and the chemistry here essentially paralleled that shown for cyfusine (17) with the key lactam enolate addition (of 18) also taking place in quantitative yield.

Scheme 4 Synthesis of cyfusine (17) and 4-fluorocyfusine (19)

In summary, our recently developed route to cytisine, which is based on addition of a lactam enolate to a pyridone, is flexible and offers access to a series of structural modifications, including the otherwise inaccessible 4-halo variants of both cytisine and cyfusine. Access to 4-bromocytisine (12), as well as intermediates 10 and 11, offers a highly versatile functional handle, and Pd(0)-mediated cross-coupling and heteroatom couplings at C(4) are readily achievable. Biological studies to characterize the nicotinic affinity and functional profiles of the compounds reported in this paper, and related C(4) derivatives, are under way and will be reported shortly.

Acknowledgment

The authors thank the EPSRC and MIUR (PRIN # 20072BTSR2) for financial support.

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)

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]+.

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

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)

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]+.

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

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Figure 1

Scheme 1 Lactam enolate addition approach to cytisine (1)

Scheme 2 Synthesis of 4-fluorocytisine (8)

Scheme 3 Synthesis of 4-bromocytisine (12) and 4-chlorocytisine (13)

Scheme 4 Synthesis of cyfusine (17) and 4-fluorocyfusine (19)

Scheme 5 Synthesis of 4-fluoropyridone (4)

Figure 2