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DOI: 10.1055/s-0030-1259006
Lactam Enolate-Pyridone Addition: Synthesis of 4-Halocytisines
Publication History
Publication Date:
14 October 2010 (online)
![](https://www.thieme-connect.de/media/synlett/201018/lookinside/thumbnails/10.1055-s-0030-1259006-1.jpg)
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 and Notes
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]
)
![](https://www.thieme-connect.de/media/synlett/201018/d255_s5.gif)
Scheme 5 Synthesis of 4-fluoropyridone (4)
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]+.
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]+.
![](https://www.thieme-connect.de/media/synlett/201018/d255_f2.gif)
Figure 2