Lactam enolate-pyridone addition: Synthesis of 4-halocytisines

Article abstract of DOI:10.1055/s-0030-1259006

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.

Full text of DOI:10.1055/s-0030-1259006

LETTER
2789
Lactam Enolate–Pyridone Addition: Synthesis of 4-Halocytisines
S
ynthesis of
4
a
t
a
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK
Fax +44(117)9251295; E-mail: t.gallagher@bristol.ac.uk
Università degli studi di Milano, Dipartimento di Scienze Farmaceutiche ‘Pietro Pratesi’, via L. Mangiagalli, 20133 Milan, Italy
b
Received 14 September 2010
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-Substi-
tuted cytisines are not accessible from cytisine itself7 and
halogenated variants at this site therefore present a chal-
lenge and a gap in terms of structure–activity determina-
tion.
Abstract: The application of a lactam enolate–pyridone addition
sequence, originally developed for cytisine, has been applied suc-
cessfully 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 po-
tent, high-affinity ligand for neuronal acetylcholine recep-
tors, behaving as a partial agonist at a4b2 and a full
agonist at a7.1 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 Europe2) but also as
the drug discovery lead for varenicline (2), which was
launched by Pfizer in 2006.3
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 chromatog-
raphy. Exposure of 5 to LiHMDS promoted enolization
and intramolecular 1,6-addition to give a 2.3:1 mixture of
a- and b-adducts a-6 and b-6; only a-6 is shown and these
assignments were based on NOE experiments. As in ear-
lier studies,4d subsequent oxidation of 6 was dependent on
the configuration at C(6), with the a-adduct a-6 undergo-
ing MnO2-mediated oxidation (much more rapidly than
diastereomer b-6) to re-establish the pyridone oxidation
level. Selective lactam reduction of 7 followed by N-
debenzylation gave 4-fluoropyridone 811 in 21% overall
yield from 3 (based on conversion of a-6 only).
NH
11
NH
O
N
10
N
3
7
8
N
4
cytisine (1)
varenicline (2)
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
O
HN
NBn
NBn
NBn
Br
O
O
F
O
O
O
NBn
NBn
NH
4
LiHMDS
100%
N
N
LiO
O
O
O
O
3 steps
K2CO3
73%
6
N
N
N
quant.
yield
F
3
5
H
α-6
F
H
MnO2
100%
1
Scheme 1 Lactam enolate addition approach to cytisine (1)
NH
N
NBn
O
O
O
Pd(OH)2
H2
BH3⋅THF
N
Mechanistic studies relating to this process have been re-
ported recently4d 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 vari-
ants of cytisine. This includes the application of the lac-
tam enolate/pyridone addition strategy to provide a new
entry to cyfusine, a ‘deconstructed’ cytisine variant origi-
nally reported by Yohannes and co-workers.5
42% overall
8
7
F
F
Scheme 2 Synthesis of 4-fluorocytisine (8)
Extending this chemistry to 4-bromocytisine (12) then re-
quired simple variation of the pyridone component
(Scheme 3). A similar sequence to that outlined in
Scheme 2, based on 4-bromopyridone (9), provided tricy-
cle 10 after MnO2 oxidation. However, the lability of the
4-bromo substituent meant that an alternative deprotec-
SYNLETT 2010, No. 18, pp 2789–2791
x
x
.x
x
.2
0
1
0
Advanced online publication: 14.10.2010
DOI: 10.1055/s-0030-1259006; Art ID: D25510ST
© Georg Thieme Verlag Stuttgart · New York

2790
P. Durkin et al.
LETTER
O
tion sequence was necessary. Borane reduction of 10 pro-
ceeded smoothly and subsequent debenzylation of
piperidine 11 was achieved using 1-chloroethyl chlorofor-
mate, followed by methanolysis. Interestingly, this se-
quence provided two separable products, 4-bromocytisine
(12) and the corresponding 4-chlorocytisine (13) in a 3:1
ratio and in 69% overall yield.12
NBn
NBn
NBn
HN
O
O
O
O
O
N
LiHMDS
100%
Br
N
H
K2CO3
61%
14
15
β-16 (major)
MnO2
68%
NH
NBn
O
NBn
NBn
O
O
O
O
O
Pd(OH)2 BH3⋅THF
H2
O
O
N
(i) LiHMDS
3
N
N
N
HN
K2CO3
69%
(ii) MnO2
80%
36% overall
cyfusine (17)
NBn
Br
10
BH3⋅THF
NBn
Br
Br
9
NH
O
O
O
4
4 steps
N
14
N
NH
NH
K2CO3
75%
O
O
O
14% overall
F
N
N
MeCH(Cl)OCOCl
N
18
19
F
then MeOH
69%
(see text)
Scheme 4 Synthesis of cyfusine (17) and 4-fluorocyfusine (19)
Br
Cl
12
13
11
Br
Scheme 3 Synthesis of 4-bromocytisine (12) and 4-chlorocytisine
(13)
Acknowledgment
The authors thank the EPSRC and MIUR (PRIN # 20072BTSR2)
for financial support.
The halide exchange (11 → 12 and 13) presumably arises
during the initial N-acylation–debenzylation step as the
halide residues both survive methanolysis.
References and Notes
Cyfusine (17)5 represents an example of a ‘deconstructed’
cytisine and we now report a new approach to both cy-
fusine and 4-fluorocyfusine (19) based on lactam enolate–
pyridone addition (Scheme 4). The requisite pyrrolidino-
ne precursor 14 has been reported previously13,4d and cy-
clization of lactam 15 proceeded in quantitative yield to
give 16 as a 1:3 mixture of a- and b-isomers; only the ma-
jor component (b-16) is shown. In this case, and presum-
ably because 16 is conformationally less rigid than the
piperidinone variants (e.g., 6), both the a- and b-16 under-
went smooth oxidation. Lactam reduction and conven-
tional 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-fluorocy-
fusine (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.
(1) Synthetic chemistry: (a) Stead, D.; O’Brien, P. Tetrahedron
2007, 63, 1885. Medicinal chemistry and pharmacology:
(b) Jensen, A. A.; Frølund, B.; Lijefors, T.; Krogsgaard-
Larsen, P. J. Med. Chem. 2005, 48, 4705. (c) Pabreza, L.
A.; Dhawan, S.; Kellar, K. J. Mol. Pharmacol. 1991, 39, 9.
(d) Papke, R. L.; Heinemann, S. F. Mol. Pharmacol. 1994,
45, 142.
(2) Etter, J. F. Arch. Intern. Med. 2006, 166, 1553.
(3) (a) Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.;
Arnold, E. P.; Huang, J.; Sands, S. B.; Davis, T. I.; Lebel, L.
A.; Fox, C. B.; Shrikhande, A.; Heym, J. H.; Schaeffer, E.;
Rollema, H.; Lu, Y.; Mansbach, R. S.; Chambers, L. K.;
Rovetti, C. C.; Schulz, D. W.; Tingley, F. D.; O’Neill, B. T.
J. Med. Chem. 2005, 48, 3474. (b) Coe, J. W.; Vetelino, M.
G.; Bashore, C. G.; Wirtz, M. C.; Brooks, P. R.; Arnold, E.
P.; Lebel, L. A.; Fox, C. B.; Sands, S. B.; Davis, T. I.;
Schulz, D. W.; Rollema, H.; Tingley, F. D.; O’Neill, B. T.
Bioorg. Med. Chem. Lett. 2005, 15, 2974. (c) Mihalak, K.
B.; Carroll, F. I.; Luetje, C. W. Mol. Pharmacol. 2006, 70,
801. (d) Coe, J. W.; Rollema, H.; O’Neill, B. T. Ann. Rep.
Med. Chem. 2009, 44, 71.
In summary, our recently developed route to cytisine,
which is based on addition of a lactam enolate to a pyri-
done, 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)-me-
diated cross-coupling and heteroatom couplings at C(4)
are readily achievable. Biological studies to characterize
the nicotinic affinity and functional profiles of the com-
pounds reported in this paper, and related C(4) deriva-
tives, are under way and will be reported shortly.
(4) (a) Botuha, C.; Galley, C. M. S.; Gallagher, T. Org. Biomol.
Chem. 2004, 2, 1825. (b) Gray, D.; Gallagher, T. Angew.
Chem. Int. Ed. 2006, 45, 2419. (c) Frigerio, F.; Haseler,
C. A.; Gallagher, T. Synlett 2010, 729. (d) Gallagher, T.;
Derrick, I.; Durkin, P. M.; Haseler, C. A.; Hirschhäuser, C.;
Magrone, P. J. Org. Chem. 2010, 75, 3766.
(5) Yohannes, D.; Procko, K.; Lebel, L. A.; Fox, C. B.; O’Neill,
B. T. Bioorg. Med. Chem. Lett. 2008, 18, 2316.
(6) (a) Imming, P.; Klaperski, P.; Stubbs, M. T.; Seitz, G.;
Gündisch, D. Eur. J. Med. Chem. 2001, 36, 375. (b) Slater,
Y. E.; Houlihan, L. M.; Maskell, P. D.; Exley, R.; Bermudez,
I.; Lukas, R. J.; Valdivia, A. C.; Cassels, B. K.
Neuropharmacol. 2003, 44, 503.
(7) Chellappan, S. K.; Xiao, Y.; Tueckmantel, W.; Kellar, K. J.;
Kozikowski, A. P. J. Med. Chem. 2006, 49, 2673.
Synlett 2010, No. 18, 2789–2791 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Halocytisines
Data for 4-Chlorocytisine (13)
2791
(8) Leznoff, C. C.; Svirskaya, P. I.; Yedidia, V.; Miller, J. M.
J. Heterocycl. Chem. 1985, 22, 145.
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 C11H1435ClN2O:
225.0795; found: 225.0784 [M + H]+.
(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 procedure10 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)
(13) Stanetty, P.; Turner, M.; Mihovilovic, M. D. Molecules
2005, 10, 367; and ref. 4d.
(14) Data for Cyfusine (17)
Cl
OMe
O
(i) MeONa
Cu(s)
1H NMR (400 MHz, CDCl3): d = 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): d = 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
TMSCl
NaI
N
N
HN
(ii) NaNO2,
HBF4
NH2
F
F
I
4
Scheme 5 Synthesis of 4-fluoropyridone (4)
(10) (a) Urban, R.; Schnider, O. Helv. Chim. Acta 1964, 47, 363.
(b) 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): d = 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): d = 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 =
(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): d = 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): d = 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): d = –97.14 (m). HRMS: m/z
calcd for C10H12FN2O: 195.0928; found: 195.0930 [M + H]+.
19.0 Hz, C=O, C2), 169.9 (d, J = 264.0 Hz, CF, C4). 19
F
NMR (376 MHz, CDCl3): d = –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): 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), 3.86 (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): d = 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 C11H1379BrN2O:
268.0211; found: 268.0216 [M]+.
7
NH
8
O
1
N
8a
3
5b
5a
5
F
19
Figure 2
Synlett 2010, No. 18, 2789–2791 © Thieme Stuttgart · New York

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